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Journal articles on the topic 'Docetaxel resistance'
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1
Kroon, Jan, Martin Puhr, Jeroen T. Buijs, Geertje van der Horst, Daniëlle M. Hemmer, Koen A. Marijt, Ming S. Hwang, et al. "Glucocorticoid receptor antagonism reverts docetaxel resistance in human prostate cancer." Endocrine-Related Cancer 23, no. 1 (October 19, 2015): 35–45. http://dx.doi.org/10.1530/erc-15-0343.
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Resistance to docetaxel is a major clinical problem in advanced prostate cancer (PCa). Although glucocorticoids (GCs) are frequently used in combination with docetaxel, it is unclear to what extent GCs and their receptor, the glucocorticoid receptor (GR), contribute to the chemotherapy resistance. In this study, we aim to elucidate the role of the GR in docetaxel-resistant PCa in order to improve the current PCa therapies. GR expression was analyzed in a tissue microarray of primary PCa specimens from chemonaive and docetaxel-treated patients, and in cultured PCa cell lines with an acquired docetaxel resistance (PC3-DR, DU145-DR, and 22Rv1-DR). We found a robust overexpression of the GR in primary PCa from docetaxel-treated patients and enhanced GR levels in cultured docetaxel-resistant human PCa cells, indicating a key role of the GR in docetaxel resistance. The capability of the GR antagonists (RU-486 and cyproterone acetate) to revert docetaxel resistance was investigated and revealed significant resensitization of docetaxel-resistant PCa cells for docetaxel treatment in a dose- and time-dependent manner, in which a complete restoration of docetaxel sensitivity was achieved in both androgen receptor (AR)-negative and AR-positive cell lines. Mechanistically, we demonstrated down-regulation of Bcl-xL and Bcl-2 upon GR antagonism, thereby defining potential treatment targets. In conclusion, we describe the involvement of the GR in the acquisition of docetaxel resistance in human PCa. Therapeutic targeting of the GR effectively resensitizes docetaxel-resistant PCa cells. These findings warrant further investigation of the clinical utility of the GR antagonists in the management of patients with advanced and docetaxel-resistant PCa.
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ILHAN, Suleyman. "Effect of interleukin-8 on docetaxel resistance in prostate cancer cells: insights into the role of multidrug resistance 1 protein modulation." Cancer Insight 2, no. 1 (June 14, 2023): 53–67. http://dx.doi.org/10.58567/ci02010004.
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Although docetaxel treatment yields a high survival rate for prostate cancer (PCa), resistance eventually develops in many patients. Understanding the underlying mechanisms of docetaxel resistance is essential for improving treatment strategies. Cytokines, which play a role in cell signaling and immune responses, have been implicated in drug resistance mechanisms. The study revealed that interleukin-8 (IL-8) was consistently overexpressed in both docetaxel-resistant PCa cell lines. Thus, the expression levels of cytokines released from docetaxel-sensitive (PC-3- and DU-145) and resistant (PC-3/R-DU-145/R) PCa cells were compared. IL-8 was found to be commonly expressed in resistant cell lines. This finding led to the hypothesis that IL-8 could play a key role in mediating PCa cell resistance to docetaxel. IL-8 siRNA treatment increased docetaxel sensitivity in both resistant cells. To demonstrate the mechanism of IL-8-related resistance, MDR1 expression was evaluated. After IL-8 siRNA treatment MDR1 expression was reduced in both resistant cells suggesting that IL-8 regulates the docetaxel resistance of PCa cells via modulation of multidrug resistance 1 (MDR1). By expanding the knowledge of the cytokines and their effect mechanisms, novel approaches can be developed for the treatment of docetaxel-resistant prostate cancer. Further investigations into the role of IL-8 in docetaxel resistance could offer valuable insights into the development of effective treatment strategies for PCa patients.
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Shen, Weiwei, Hailin Pang, Jiayu Liu, Jing Zhou, Feng Zhang, Lele Liu, Ningqiang Ma, Ning Zhang, Helong Zhang, and Lili Liu. "EpithelialMesenchymal Transition Contributes to Docetaxel Resistance in Human Non-Small Cell Lung Cancer." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 22, no. 1 (October 23, 2014): 47–55. http://dx.doi.org/10.3727/096504014x14098532393473.
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Lung cancer is an aggressive malignancy with high morbidity and mortality. Chemotherapy has always been the principal treatment measure, but its acquired resistance becomes a critical problem. In the current study, we established a new docetaxel-resistant human non-small lung cancer (NSCLC) cell line A549/Docetaxel. The resistance index (RI) of A549/Docetaxel cells and A549 induced by TGF- to docetaxel were 8.91 and 11.5, respectively. Compared to the parental A549 cells, the multiplication time of A549/Docetaxel was prolonged, the proportion of the cell cycle in the S phase decreased while that in the G1 phase increased, and apoptotic rate was much lower. The morphology of the resistant cells eventuated epithelialmesenchymal transition (EMT), which was confirmed by the higher expression of fibronectin, vimentin (mesenchymal markers), and lower expression of E-cadherin (epithelial marker) at mRNA and proteins levels. Furthermore, the representative markers for docetaxel resistance were examined, including ABCB1 (MDR1), Bcl-2, Bax, and tubulin, to figure out the mechanisms of the resistance of A549/Docetaxel. In summary, we have established a typical docetaxel-resistant human NSCLC cell line A549/Docetaxel, and it was suggested that the multidrug resistance of A549/Docetaxel was related to EMT.
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Francini, Edoardo, Fang-Shu Ou, Justin Rhoades, Eric G. Wolfe, Edward P. O’Connor, Gavin Ha, Gregory Gydush, et al. "Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer." Cancers 13, no. 16 (August 12, 2021): 4055. http://dx.doi.org/10.3390/cancers13164055.
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There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.
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Zu, Shulu, Weiming Ma, Pan Xiao, Yazhou Cui, Tianjia Ma, Chunwen Zhou, and Huaiqiang Zhang. "Evaluation of Docetaxel-Sensitive and Docetaxel-Resistant Proteomes in PC-3 Cells." Urologia Internationalis 95, no. 1 (2015): 114–19. http://dx.doi.org/10.1159/000351263.
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Objectives: Docetaxel was the first drug with proven survival benefit in men with castration-resistant prostate cancer. Acquired resistance to docetaxel precedes fatality in castration-resistant prostate cancer. The aims of this study were to evaluate docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells, and to investigate the molecular mechanism of docetaxel-resistant PC-3 cells. Methods: Docetaxel-resistant PC-3 cells were developed by docetaxel dose escalation. The global profiling of the protein expression was investigated in docetaxel-sensitive and docetaxel-resistant proteomes in PC-3 cells using 2-dimensional polyacrylamide gel electrophoresis/matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Results: Forty-nine differential proteins were found in docetaxel-resistant PC-3 cells in comparison with docetaxel-sensitive PC-3 cells. Expression in 29 proteins was upregulated, whereas expression in 20 proteins was downregulated. ATP synthase and galectin-1 were involved in the formation of tumor vessels; calreticulin, cathepsin D, and cofilin were involved in tumor metastasis, and GRP78 (78-kDa glucose-regulated protein) and microtubule-associated protein-6 were involved in drug resistance of tumor. Conclusion: It is suggested that a proteomic expression difference exists between docetaxel-sensitive and docetaxel-resistant PC-3 cells, which would be helpful for further understanding the molecular mechanisms of docetaxel resistance in PC-3 cells.
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Lima, Thiago S., Diego Iglesias-Gato, Luciano D. O. Souza, Jan Stenvang, Diego S. Lima, Martin A. Røder, Klaus Brasso, and José M. A. Moreira. "Molecular Profiling of Docetaxel-Resistant Prostate Cancer Cells Identifies Multiple Mechanisms of Therapeutic Resistance." Cancers 13, no. 6 (March 14, 2021): 1290. http://dx.doi.org/10.3390/cancers13061290.
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Docetaxel—a taxane-based chemotherapeutic agent—was the first treatment to demonstrate significant improvements in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, the response to docetaxel is generally short-lived, and relapse eventually occurs due to the development of resistance. To explore the mechanisms of acquired docetaxel resistance in prostate cancer (PCa) and set these in the context of androgen deprivation therapy, we established docetaxel-resistant PCa cell lines, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line. We generated two docetaxel-resistant LNCaPR and C4-2BR sub-lines, with IC50 values 77- and 50-fold higher than those of the LNCaP and C4-2B parental cells, respectively. We performed gene expression analysis of the matched sub-lines and found several alterations that may confer docetaxel resistance. In addition to increased expression of ABCB1, an ATP-binding cassette (ABC) transporter, and a well-known gene associated with development of docetaxel resistance, we identified genes associated with androgen signaling, cell survival, and overexpression of ncRNAs. In conclusion, we identified multiple mechanisms that may be associated with the development of taxane drug resistance in PCa. Actioning these mechanisms could provide a potential approach to re-sensitization of docetaxel-resistant PCa cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with mCRPC.
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Bukhari, Nedal, Kylea R. Potvin, D. Scott Ernst, Lori Sax, and Eric Winquist. "Early docetaxel-resistance in metastatic hormone-sensitive prostate cancer." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 260. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.260.
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260 Background: The addition of docetaxel to standard androgen deprivation therapy (ADT) has been shown to improve the survival of men with metastatic hormone-sensitive prostate cancer (MHSPC) (Sweeney 2015, James 2016). We noticed PSA progression in some of our patients (pts) during docetaxel treatment and reviewed their outcomes. Methods: Men with MHSPC treated with docetaxel were identified from an electronic oncology pharmacy database. Eligible pts were prescribed docetaxel for metastatic adenocarcinoma of the prostate within 120 days of initiation of ADT. Pts with castration-resistant disease (CRPC), other histologies, and those without metastatic disease were excluded. Demographic, clinical, treatment and outcome data were extracted retrospectively from electronic medical records. Results: 31 eligible pts with MHSPC treated with docetaxel between August 2014 and July 2016 were identified. Median age was 65 years (53-83) and 28 (90%) had high-volume disease as defined by Sweeney et al (2015). Nadir PSA levels 6-7 months from ADT initiation were < 0.2, 0.2-4, and > 4 ng/mL in 29.0%, 36.7% and 36.7%, respectively. At median follow up of 85 weeks, 45.2% of pts had progressed to CRPC and 22.6% had died. Median time to CRPC was 59 weeks and median overall survival was 85 weeks. Seven pts with high-volume disease (25%) had PSA progression while receiving docetaxel treatment. The median overall survival of this group was 26 weeks (17 to 106+) and six have died. Three had visceral metastases. Nadir PSA was < 0.2 (1 pt), 0.2-4 (2 pts) and > 4 ng/mL (4 pts). After docetaxel 2 pts received BSC alone and 5 pts had 1st-line CRPC therapy. No response to abiraterone/enzalutamide was seen (3 pts). Two pts who discontinued docetaxel immediately at PSA progression and were switched to alternative chemotherapy survived > 1 year. Conclusions: A subset of men with MHSPC has lethal docetaxel-resistant disease characterized by early PSA rise. It is important to recognize these patients, but it is not clear if standard CRPC therapies are effective. An immediate early switch to alternative chemotherapy may be helpful. Further research to predict early docetaxel resistance, characterize response to current therapies and identify more effective treatment is needed.
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Gruber, Martina, Lavinia Ferrone, Martin Puhr, Frédéric R. Santer, Tobias Furlan, Iris E. Eder, Natalie Sampson, Georg Schäfer, Florian Handle, and Zoran Culig. "p300 is upregulated by docetaxel and is a target in chemoresistant prostate cancer." Endocrine-Related Cancer 27, no. 3 (March 2020): 187–98. http://dx.doi.org/10.1530/erc-19-0488.
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Administration of the microtubule inhibitor docetaxel is a common treatment for metastatic castration-resistant prostate cancer (mCRPC) and results in prolonged patient overall survival. Usually, after a short period of time chemotherapy resistance emerges and there is urgent need to find new therapeutic targets to overcome therapy resistance. The lysine-acetyltransferase p300 has been correlated to prostate cancer (PCa) progression. Here, we aimed to clarify a possible function of p300 in chemotherapy resistance and verify p300 as a target in chemoresistant PCa. Immunohistochemistry staining of tissue samples revealed significantly higher p300 protein expression in patients who received docetaxel as a neoadjuvant therapy compared to control patients. Elevated p300 expression was confirmed by analysis of publicly available patient data, where significantly higher p300 mRNA expression was found in tissue of mCRPC tumors of docetaxel-treated patients. Consistently, docetaxel-resistant PCa cells showed increased p300 protein expression compared to docetaxel-sensitive counterparts. Docetaxel treatment of PCa cells for 72 h resulted in elevated p300 expression. shRNA-mediated p300 knockdown did not alter colony formation efficiency in docetaxel-sensitive cells, but significantly reduced clonogenic potential of docetaxel-resistant cells. Downregulation of p300 in docetaxel-resistant cells also impaired cell migration and invasion. Taken together, we showed that p300 is upregulated by docetaxel, and our findings suggest that p300 is a possible co-target in treatment of chemoresistant PCa.
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Zhao, Song, Ilsa Coleman, Roger Coleman, and Peter Nelson. "Association of PARP inhibitors and docetaxel resistance through suppressing a tumor microenvironment-associated secretory program." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22212-e22212. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22212.
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e22212 Background: Acquired resistance to therapeutics accounts for the majority of treatment failures in metastatic cancer. In response to genotoxic stress induced by therapeutics such as radiation and chemotherapy, tumor microenvironment (TME) undergoes marked molecular alterations manifested by increased secretion of cytokines and growth factors, which in turn promote tumor growth, facilitate epithelial-mesenchymal transition, and ultimately result in resistance to chemotherapy. Fibroblasts are a major component of TME and a primary source of cytokines and growth factor secretion following damage. Preliminary results from our lab indicated PARP1 may be involved in regulating this secretory program. We hypothesized that PARP inhibition would suppress the TME-associated secretory program and thereby overcome chemotherapy resistance. Methods: Transcript profiles of cytokines and growth factors were analyzed with quantitative real-time PCR and cDNA microarrays in prostate fibroblasts after treatment with radiation or docetaxel, in combination with one of three PARP inhibitors (PARPi). We evaluated the effects of the docetaxel-induced fibroblast secretory program, in the absence or presence of PARPi, on the proliferation and drug sensitivity of prostate cancer cell lines. Results: Similar to radiation, docetaxel induced the secretion of cytokines and growth factors in prostate fibroblasts. PARP1 was activated by docetaxel treatment. Exposure to PARPi suppressed the docetaxel-induced secretory program. Further analysis suggested that PARPi abrogates activation of p38MAPK pathway. While conditioned medium from docetaxel-treated prostate fibroblasts stimulated growth and chemotherapy resistance, the addition of PARPi attenuated these effects. Conclusions: Docetaxel induces extracellular secretion of pro-tumorigenic cytokines and growth factors by components of the TME. PARP inhibitors attenuated docetaxel resistance through suppression of this secretory program, supporting a new mechanism of action for this class of drugs. Combinatorial use of cytotoxic agents and microenvironment-directed therapies may reduce treatment resistance.
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Wróbel, Tomasz, Marcin Luty, Jessica Catapano, Elżbieta Karnas, Małgorzata Szczygieł, Katarzyna Piwowarczyk, Damian Ryszawy, et al. "CD44+ cells determine fenofibrate-induced microevolution of drug-resistance in prostate cancer cell populations." Stem Cells 38, no. 12 (October 2, 2020): 1544–56. http://dx.doi.org/10.1002/stem.3281.
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Abstract Combinations of metabolic blockers (including fenofibrate) with chemotherapeutic drugs interfere with the drug-resistance of prostate cancer cells. However, their effect on cancer stem cells-dependent microevolution of prostate cancer malignancy remains unaddressed. Here, we hypothesize that the combined docetaxel/fenofibrate treatment prompts the selective expansion of cancer stem cells that affects the microevolution of their progenies. Accordingly, we adapted a combined in vitro/in vivo approach to identify biological and therapeutic consequences of this process. Minute subpopulations of docetaxel-resistant CD133high and/or CD44high cancer stem cell-like (SCL) cells were found in prostate cancer DU145 and PC3 cell populations. When pretreated with docetaxel, they readily differentiated into docetaxel-resistant CD44negative “bulk” cells, thus accounting for the microevolution of drug-resistant cell lineages. Combined docetaxel/fenofibrate treatment induced the generation of poly(morpho)nuclear giant cells and drug-resistant CD44high SCL cells. However, the CD44negative offspring of docetaxel- and docetaxel/fenofibrate-treated SCLs remained relatively sensitive to the combined treatment, while retaining enhanced resistance to docetaxel. Long-term propagation of drug-resistant SCL-derived lineages in the absence of docetaxel/fenofibrate resulted in their reverse microevolution toward the drug-sensitivity and invasive phenotype. Consequently, prostate tumors were able to recover from the combined docetaxel/fenofibrate stress after the initial arrest of their expansion in vivo. In conclusion, we have confirmed the potential of fenofibrate for the metronomic treatment of drug-resistant prostate tumors. However, docetaxel/fenofibrate-induced selective expansion of hyper-resistant CD44high SCL prostate cells and their “bulk” progenies prompts the microevolution of prostate tumor drug-resistance. This process can limit the implementation of metabolic chemotherapy in prostate cancer treatment.
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Liu, Rong-Zong, Mansi Garg, Xiao-Hong Yang, and Roseline Godbout. "Docetaxel-Induced Cell Death Is Regulated by a Fatty Acid-Binding Protein 12-Slug-Survivin Pathway in Prostate Cancer Cells." International Journal of Molecular Sciences 25, no. 17 (September 6, 2024): 9669. http://dx.doi.org/10.3390/ijms25179669.
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Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often accompanies prostate cancer progression. Attempts to overcome resistance to docetaxel by combining docetaxel with other biological agents have been mostly unsuccessful. A better understanding of the mechanisms underlying docetaxel resistance may provide new avenues for the treatment of advanced PCa. We have previously found that the fatty acid-binding protein 12 (FABP12)-PPARγ pathway modulates lipid-related bioenergetics and PCa metastatic transformation through induction of Slug, a master driver of epithelial-to-mesenchymal transition (EMT). Here, we report that the FABP12-Slug axis also underlies chemoresistance in PCa cells. Cell sensitivity to docetaxel is markedly suppressed in FABP12-expressing cells, along with induction of Survivin, a typical apoptosis inhibitor, and inhibition of cleaved PARP, a hallmark of programmed cell death. Importantly, Slug depletion down-regulates Survivin and restores cell sensitivity to docetaxel in FABP12-expressing cells. Finally, we also show that high levels of Survivin are associated with poor prognosis in PCa patients, with FABP12 status determining its prognostic significance. Our research identifies a FABP12-Slug-Survivin pathway driving docetaxel resistance in PCa cells, suggesting that targeting FABP12 may be a precision approach to improve chemodrug efficacy and curb metastatic progression in PCa.
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Shimizu, Yasuomi, Satoshi Tamada, Minoru Kato, Yukiyoshi Hirayama, Yuji Takeyama, Taro Iguchi, Marianne Sadar, and Tatsuya Nakatani. "Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy." Journal of Clinical Medicine 7, no. 11 (November 16, 2018): 444. http://dx.doi.org/10.3390/jcm7110444.
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Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes.
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Liu, Xiao Dong, Yi Ju Hou, Lin Zhang, and Hui Ling Cao. "Compound Injection of Shenqi as a Reversal Drug on Docetaxel Resistant Human Lung Adenocarcinoma Cell A549/DTX." Advanced Materials Research 926-930 (May 2014): 1054–57. http://dx.doi.org/10.4028/www.scientific.net/amr.926-930.1054.
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To investigate the effect and the mechanism of compound injection of Shenqi (Codonopsis and Astragalus) on Docetaxel resistance of human lung adenocarcinoma cell A549/ DTX. The cytotoxicities of Shenqi Injection were assayed with the MTT method, the effects of Shenqi Injection on apoptosis induced by Docetaxel in A549/ DTX was examined by flow cytometry (FCM). The expression levels of apoptosis regulator Bc1-2 and Bax were detected by Western blot. After treatment with Shenqi Injection for 24 hours, results showed that 15 μL / mL Shenqi Injection significantly increased toxicity of Docetaxel on A549/DTX. Shenqi Injection could reverse the Docetaxel resistance in A549/ DTX in vitro. The drug resistance reversal index (RI) was equal to 2.71 analyzed with MTT method. Shenqi Injection could enhance the apoptosis effect of Docetaxel on A549/DTX. We conclude that Shenqi Injection can reverse the drug resistance on A549/DTX, and its mechanism is to promote apoptosis may be related with the up-regulation of Bc1-2 expression and down-regulation of Bax expression.
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Song, Liankun, Vyvyan Nguyen, Jun Xie, Matthew Tippin, Le TP Truong, Christopher A. Blair, Beverly Wang, Edward Uchio, and Xiaolin Zi. "Abstract 1687: ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1687. http://dx.doi.org/10.1158/1538-7445.am2023-1687.
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Abstract Docetaxel has been the standard first-line chemotherapy for lethal metastatic prostate cancer (mPCa) since 2004, but the resistance to docetaxel treatment is common. The molecular mechanisms of docetaxel resistance remain largely unknown and could be amenable to interventions that mitigate resistance. We have recently discovered that several docetaxel resistant mPCa cell lines exhibit less uptake of cellular copper and express markedly higher levels of ATP7B protein without significant changes in the protein expression levels of other copper transporters, such as ATPase copper transporting alpha (ATP7A) and high affinity copper uptake protein 1 (CTR1). Knock-down of ATP7B by silencing RNAs sensitized docetaxel resistant-mPCa cells to the growth inhibitory and apoptotic effects of docetaxel. Importantly, deletions of ATP7B in mPCa tissues predict significantly better survival of patients after their first chemotherapy than those with wild-type ATP7B (P = 0.0006). In addition, Disulfiram (DSF), an FDA approved drug for treatment of alcohol dependence, in combination with copper, significantly enhanced the in vivo antitumor effects of docetaxel in a docetaxel resistant xenograft tumor model. Our analyses also revealed that DSF and copper engaged with ATP7B to decrease protein levels of COMM domain-containing protein 1 (COMMD1), S-phase kinase associated protein 2 (Skp2) and clusterin and markedly increase protein expression of cyclin-dependent kinase inhibitor 1 (p21/WAF1). Taken together, our results suggest that ATP7B is a clinically relevant and key target for improving the efficacy of docetaxel for treatment of mPCa. Citation Format: Liankun Song, Vyvyan Nguyen, Jun Xie, Matthew Tippin, Le TP Truong, Christopher A. Blair, Beverly Wang, Edward Uchio, Xiaolin Zi. ATPase copper transporting beta (ATP7B) contributes to acquired docetaxel resistance in human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1687.
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Yin, Beibei, Ping Lu, Jing Liang, Wei Zhang, Meng Xin, Ke Pei, and Yan Li. "The ABCB1 3435C > T polymorphism influences docetaxel transportation in ovarian cancer." Journal of International Medical Research 47, no. 10 (September 6, 2019): 5256–69. http://dx.doi.org/10.1177/0300060519870354.
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Objective To investigate the effect of the ATP-binding cassette transporter superfamily B member 1 gene ( ABCB1) 3435C > T single nucleotide polymorphism (SNP) on docetaxel transportation in ovarian cancer cells. Methods ES-2 and SKOV3 cells were transfected with an ABCB1 3435C > T recombinant plasmid, and mRNA expression was detected by real-time PCR. The MTT assay was used to detect the toxicity of docetaxel. High-performance liquid chromatography determined the drug concentration in different cell models to evaluate intracellular accumulation, and a transmembrane resistance experiment was used to assess permeability and evaluate the effect of P-gp activity on drug transportation. A tumor-bearing mouse model was established to evaluate the effect of ABCB1 3435C > T on docetaxel resistance. Results P-gp was overexpressed in cells transfected with the ABCB1 3435C > T plasmid, leading to a significant increase in drug resistance to docetaxel. ABCB1 3435C/wild-type transfection significantly promoted the transport of docetaxel mediated by P-gp compared with ABCB1 3435T/mutant transfection. Conclusion P-gp encoded by the ABCB1 variant allele appears to be more efficient at transporting docetaxel compared with the wild-type allele. The ABCB1 3435C > T SNP dramatically affected the efflux ability of P-gp against docetaxel, and may influence P-gp expression and activity.
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Riedel, R. F., A. Porrello, E. Chenette, A. Potti, J. R. Nevins, and P. G. Febbo. "A genomic approach to identify mechanisms associated with chemotherapy resistance." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 2534. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.2534.
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2534 Background: Gene expression profiling has shown an ability to predict chemotherapeutic response (Potti et al. Nature Medicine 2006). Building on this work, we used a genomic strategy to explore the biology associated with the development of chemotherapy resistance and sought to determine if disease context impacted results. Methods: Gene set enrichment analysis (GSEA) was performed on expression data for NCI60 cell lines sensitive and resistant to specific chemotherapeutic agents (adriamycin, cyclophosphamide, docetaxel, etoposide, 5-fluoruracil, paclitaxel, topotecan). GSEA was additionally performed on a series of lung cancer cell lines with a defined sensitivity to cisplatin and docetaxel. Sensitive and resistant cell lines with individual mean and confidence intervals greater than 1SD from the mean across all samples were included. Adjusting for multiple hypothesis testing, gene sets with a false discovery rate (FDR) <0.25 were deemed statistically significant. In the discovery mode, gene sets with a nominal p-value <0.05 were also of interest. Finally, overlapping gene sets between agents were assessed. Results: Statistically-significant gene sets, representing biologic pathways associated with resistance, were identified for the various chemotherapeutic agents (i.e., cell death, erbb3, and bad pathways associated with docetaxel resistance). No gene sets with FDR <0.25 or nominal p-value <0.05 were common to all drugs. In assessing disease specific resistance, 22 lung cancer cell lines for cisplatin (15 sensitive, 7 resistant) and 14 lung cancer cell lines for docetaxel (10 sensitive, 4 resistant) were analyzed. GSEA identified the bcl-2 pathway (p<0.002) to be associated with cisplatin resistance. In contrast, the proteosome (p=0.01) and akt (p=0.02) pathways were associated with docetaxel resistance. Pathways involved in the production of V-H+-ATPase were enriched in cisplatin and docetaxel resistant lung cancer cell lines suggesting a global mechanism of resistance. Conclusions: These results support the use of a genomic approach to identify unique drug-specific and global therapeutic targets associated with the development of chemotherapy resistance. Interestingly, disease context appears important in identifying novel targets. No significant financial relationships to disclose.
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Ando, Masashi, Toru Watanabe, Kazuhiro Nagata, Masaru Narabayashi, Isamu Adachi, and Noriyuki Katsumata. "Efficacy of Docetaxel 60 mg/m2 in Patients With Metastatic Breast Cancer According to the Status of Anthracycline Resistance." Journal of Clinical Oncology 19, no. 2 (January 15, 2001): 336–42. http://dx.doi.org/10.1200/jco.2001.19.2.336.
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PURPOSE: To evaluate the efficacy of docetaxel 60 mg/m2 in metastatic breast cancer (MBC) according to the status of anthracycline resistance. PATIENTS AND METHODS: Ninety-nine patients with anthracycline-resistant MBC were treated with docetaxel 60 mg/m2 intravenously for a 90-minute period every 3 to 4 weeks. Anthracycline resistance was defined as primary and secondary resistance. Primary resistance was defined as progression during or within 6 months after completion of adjuvant anthracycline, and no MBC response to a first-line regimen that contained anthracycline. Secondary resistance was defined as progression after a documented clinical response to a first-line anthracycline treatment for MBC. Secondary resistance was further divided into three categories: (1) absolute resistance, or progression during treatment with anthracycline after a period of response; (2) relative resistance, or progression within 6 months after anthracycline administration ended; and (3) sensitive regrowth, or progression more than 6 months after the conclusion of anthracycline administration. RESULTS: The response rate in the 99 patients was 35.4% (95% confidence interval, 30.1% to 44.8%). The response rates according to the status of anthracycline resistance were as follows: primary resistance (n = 46), 19.6%; secondary resistance (n = 53), 49.1% (absolute resistance [n = 16], 56.3%); relative resistance (n = 17), 47.1%; and sensitive regrowth (n = 20), 45.0%. The median time to treatment failure in patients with primary resistance was 2.9 months, compared with 5.2 months in patients with secondary resistance (P = .0022). CONCLUSION: Docetaxel at a dose of 60 mg/m2 seemed to be effective in MBC with secondary resistance to anthracycline. The status of anthracycline resistance is important for the prediction of response to second-line treatment with docetaxel.
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Şumnulu, Deniz, and Zeynep Doğanlar. "Aba enhances the apoptotic effect of docetaxel in the multidrug-resistant DU145 prostate cancer cell line." Archives of Biological Sciences, no. 00 (2024): 31. http://dx.doi.org/10.2298/abs240812031s.
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This study aimed to induce drug resistance in DU145 prostate cancer cells by exposing them to docetaxel and mitoxantrone, and to examine the effects of combining docetaxel and abscisic acid (ABA). The IC50 values for docetaxel and mitoxantrone in non-resistant cells were 54.57 nM and 6.25 nM, respectively, rising to 808.53 nM and 50.07 nM after resistance had developed. RT-PCR analysis showed that treatment of resistant cells with 50.07 nM docetaxel and 500 ?M ABA (ABA) resulted in the following changes in gene expression: heat shock protein (HSP) 70 (0.63-fold), glucose-regulated protein 94 (GRP94) 0.33-fold, inositol-requiring transmembrane kinase endoribonuclease-1? (IRE1?) 1.62-fold, ER degradation-enhancing alpha-mannosidase-like 1 (EDEM1) 1.77-fold, X-box binding protein 1 (XBP1) 1.53-fold, p21 (2.53-fold), cellular tumor antigen p53 (p53) 2.49-fold, bcl-2-like protein 4 (Bax) 2.7-fold, and tumor necrosis factor (TNF-?) 6.35-fold. Tali? cytometry analysis showed a 47% increase in apoptotic/necrotic cells with the combined treatment of docetaxel and ABA, compared to a 26% increase with docetaxel alone. Fluorescent staining revealed that co-administration of docetaxel and ABA increases apoptosis in resistant DU145 cells compared to treatment with docetaxel alone. This study suggests that combining ABA with docetaxel could be effective in drug-resistant prostate cancer.
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Shimizu, Yasuomi, Minoru Kato, Yuji Takeyama, Kosuke Hamada, Taro Iguchi, Satoshi Tamada, and Tatsuya Nakatani. "The effect of androgen receptor splice variant 7 on the growth of castration-resistant prostate cancer and the efficacy of taxane chemotherapy." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 302. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.302.
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302 Background: Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as a mechanism associated with the development of castration-resistant prostate cancer (CRPC), but a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. We clarify the relationship between AR-V7 expression and resistance to taxanes. Furthermore, we assess the inhibitory effect of EPI-002, an antagonist of AR amino-terminal domain (NTD), to an AR-V7 driven CRPC cell line with acquired resistance to docetaxel. Methods: LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel, was developed. WST-1 assay or BrdU ELISA assay was performed to evaluate the inhibitory effect of drugs. We examined alterations of AR and AR-V7 signaling using Western blot analyses, real-time RT-qPCR and reporter gene assay. Results: LNCaP95-DR cells showed cross-resistance to cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002 had an inhibitory effect on the proliferation of LNCaP95-DR cells that was similar to that achieved with the parental LNCaP95 cells, whereas enzalutamide had no effect on the proliferation of either cell line. Conclusions: Our results suggest that EPI-002 may be an option for the treatment of AR-V7-driven CRPC that is resistant to taxanes.
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Schaaf, Zachary A., Shu Ning, Amy R. Leslie, Masuda Sharifi, Xianrui Han, Cameron Armstrong, Wei Lou, Alan P. Lombard, Chengfei Liu, and Allen C. Gao. "Therapeutic Resistance Models and Treatment Sequencing in Advanced Prostate Cancer." Cancers 15, no. 21 (November 3, 2023): 5273. http://dx.doi.org/10.3390/cancers15215273.
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Current common treatments for castration-resistant prostate cancer (CRPC) typically belong to one of three major categories: next-generation anti-androgen therapies (NGAT) including enzalutamide, abiraterone acetate, apalutamide, and darolutamide; taxane therapy represented by docetaxel; and PARP inhibitors (PARPi) like olaparib. Although these treatments have shown efficacy and have improved outcomes for many patients, some do not survive due to the emergence of therapeutic resistance. The clinical landscape is further complicated by limited knowledge about how the sequence of treatments impacts the development of therapeutic cross-resistance in CRPC. We have developed multiple CRPC models of acquired therapeutic resistance cell sublines from C4-2B cells. These include C4-2B MDVR, C4-2B AbiR, C4-2B ApaR, C4-2B DaroR, TaxR, and 2B-olapR, which are resistant to enzalutamide, abiraterone, apalutamide, darolutamide, docetaxel, and olaparib, respectively. These models are instrumental for analyzing gene expression and assessing responses to various treatments. Our findings reveal distinct cross-resistance characteristics among NGAT-resistant cell sublines. Specifically, resistance to enzalutamide induces resistance to abiraterone and vice versa, while maintaining sensitivity to taxanes and olaparib. Conversely, cells with acquired resistance to docetaxel exhibit cross-resistance to both cabazitaxel and olaparib but retain sensitivity to NGATs like enzalutamide and abiraterone. OlapR cells, significantly resistant to olaparib compared to parental cells, are still responsive to NGATs and docetaxel. Moreover, OlapR models display cross-resistance to other clinically relevant PARP inhibitors, including rucaparib, niraparib, and talazoparib. RNA-sequencing analyses have revealed a complex network of altered gene expressions that influence signaling pathways, energy metabolism, and apoptotic signaling, pivotal to cancer’s evolution and progression. The data indicate that resistance mechanisms are distinct among different drug classes. Notably, NGAT-resistant sublines exhibited a significant downregulation of androgen-regulated genes, contrasting to the stable expression noted in olaparib and docetaxel-resistant sublines. These results may have clinical implications by showing that treatments of one class can be sequenced with those from another class, but caution should be taken when sequencing drugs of the same class.
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Byun, Woong Sub, Eun Seo Bae, Jinsheng Cui, Hyen Joo Park, Dong-Chan Oh, and Sang Kook Lee. "Antitumor Activity of Pulvomycin via Targeting Activated-STAT3 Signaling in Docetaxel-Resistant Triple-Negative Breast Cancer Cells." Biomedicines 9, no. 4 (April 17, 2021): 436. http://dx.doi.org/10.3390/biomedicines9040436.
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Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the tumorigenesis and metastasis of numerous cancers, and STAT3 signaling is aberrantly activated in TNBC cells. In this study, a docetaxel-resistant TNBC cell line (MDA-MB-231-DTR) was established, and mechanisms for the antitumor activity of pulvomycin, a novel STAT3 inhibitor isolated from marine-derived actinomycete, were investigated. Levels of activated STAT3 (p-STAT3 (Y705)) increased in docetaxel-resistant cells, and knockdown of STAT3 recovered the sensitivity to docetaxel in MDA-MB-231-DTR cells. Pulvomycin effectively inhibited the proliferation of both cell lines. In addition, pulvomycin suppressed the activation of STAT3 and subsequently induced G0/G1 cell cycle arrest and apoptosis. Pulvomycin also significantly inhibited the invasion and migration of MDA-MB-231-DTR cells through the modulation of epithelial-mesenchymal transition markers. In an MDA-MB-231-DTR-bearing xenograft mouse model, the combination of pulvomycin and docetaxel effectively inhibited tumor growth through STAT3 regulation. Thus, our findings demonstrate that the combination of docetaxel and STAT3 inhibitors is an effective strategy for overcoming docetaxel resistance in TNBC.
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Sanchez, Bertha E., Nilesh Gupta, Meredith Mahan, Evelyn R. Barrack, Prem-veer Reddy, and Clara Hwang. "βIII-tubulin expression as a predictor of docetaxel resistance in metastatic castrate-resistant prostate cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e15174-e15174. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e15174.
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e15174 Background: Docetaxel is a tubulin-targeting cytotoxic that remains first-line therapy in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) even though half of pts are reported to be non-responders. A predictive marker to identify those who will benefit from docetaxel-therapy will assist clinical decision making. High βIII-tubulin (TUBB3) expression has previously been reported to correlate with lack of response to taxanes in other cancers. We evaluated TUBB3 expression as a predictor of docetaxel-resistance in mCRPC. Methods: mCRPC pts treated with at least 3 cycles of docetaxel between 1990 and 2011 were identified retrospectively. TUBB3 immunostaining was performed on archival formalin-fixed, paraffin-embedded tissue. Stain intensity was scored from 0 to 3; 2 and 3 were interpreted as positive. Rates of PSA response were compared between pts with positive (+) and negative (-) TUBB3 expression. Two definitions of PSA response were evaluated (any PSA decline and at least 50% decline). Overall survival (OS) distribution between TUBB3+ and TUBB3- pts was estimated by the Kaplan-Meier method. Results: Of 73 pts, 26 (35%) expressed TUBB3. At diagnosis, the mean age was 65.7 years and the median Gleason score was 8. At the time of docetaxel therapy, the mean age was 71.2 years, the median PSA level was 70.9 (range, 0.2-5253) and 76% had ECOG performance status ≤1. The median number of docetaxel cycles was 7 (range, 3-18). The total dose of docetaxel was not different between groups (p=0.705). The median OS was 19.2 mo. TUBB3 expression was not correlated with any clinical or pathological characteristic (age, Gleason score, stage, ECOG, PSA, LDH, alkaline phosphatase, hemoglobin, visceral disease or chemotherapy before docetaxel). 65% of TUBB3+ pts had any PSA decline compared to 89% of pts with TUBB3- (p=0.0267). 52% of TUBB3+ pts had a PSA decline of ≥ 50% compared to 70% of TUBB3- pts (p=0.0144). Median OS for TUBB3+ pts was 16.8 mo compared to 20.4 mo in TUBB3- pts (p=0.039). Conclusions: High TUBB3 expression was associated with shorter OS and lower PSA response rates in mCRPC pts treated with docetaxel. These findings need to be validated prospectively.
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&NA;. "Aberdeen researchers develop probe for docetaxel resistance." Oncology Times UK 4, no. 11 (November 2007): 7. http://dx.doi.org/10.1097/01434893-200711000-00007.
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Fenner, Annette. "Antiandrogens reverse docetaxel resistance via ABCB1 inhibition." Nature Reviews Urology 12, no. 7 (June 9, 2015): 361. http://dx.doi.org/10.1038/nrurol.2015.135.
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Lohiya, Vipin, Jeanny B. Aragon-Ching, and Guru Sonpavde. "Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer." Clinical Medicine Insights: Oncology 10s1 (January 2016): CMO.S34535. http://dx.doi.org/10.4137/cmo.s34535.
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Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development.
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Mu, Chao-Feng, Fude Cui, Yong-Mei Yin, Hyun-Jong Cho, and Dae-Duk Kim. "Docetaxel-Loaded Chitosan-Cholesterol Conjugate-Based Self-Assembled Nanoparticles for Overcoming Multidrug Resistance in Cancer Cells." Pharmaceutics 12, no. 9 (August 19, 2020): 783. http://dx.doi.org/10.3390/pharmaceutics12090783.
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Cholesteryl hemisuccinate (CHS)-conjugated chitosan (CS)-based self-assembled nanoparticles (NPs) were developed for enhancing the intracellular uptake of docetaxel in multidrug resistance (MDR)-acquired cancer cells. CHS-CS was successfully synthesized and self-aggregation, particle size, zeta potential, drug entrapment efficiency, and in vitro drug release of docetaxel-loaded CHS-CS NPs were tested. The optimized NPs had a mean hydrodynamic diameter of 303 nm, positive zeta potential of 21.3 mV, and spherical shape. The in vitro release of docetaxel from the optimized CHS-CS NPs in different pH medium (pH 6.0 and 7.4) revealed that the release was improved in a more acidic condition (pH 6.0), representing a tumor cell’s environment. The superior MDR-overcoming effect of docetaxel-loaded CHS-CS NPs, compared with docetaxel solution, was verified in anti-proliferation and cellular accumulation studies in MDR-acquired KBV20C cells. Thus, CHS-CS NPs could be potentially used for overcoming the MDR effect in anticancer drug delivery.
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Qian, Jiang, Sheliang Shen, Wei Chen, and Nianping Chen. "Propofol Reversed Hypoxia-Induced Docetaxel Resistance in Prostate Cancer Cells by Preventing Epithelial–Mesenchymal Transition by Inhibiting Hypoxia-Inducible Factor 1α." BioMed Research International 2018 (2018): 1–9. http://dx.doi.org/10.1155/2018/4174232.
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Prostate cancer is the second most frequently diagnosed cancer worldwide. Hypoxia-induced epithelial–mesenchymal transition (EMT), driven by hypoxia-inducible factor 1α (HIF-1α), is involved in cancer progression and metastasis. The present study was designed to explore the role of propofol in hypoxia-induced resistance of prostate cancer cells to docetaxel. We used the Cell Counting Kit-8 and 5-ethynyl-2′-deoxyuridine incorporation assay to measure cell viability and cell proliferation, respectively, in prostate cancer cell lines. Then, we detected HIF-1α, E-cadherin, and vimentin expression using western blotting. Propofol reversed the hypoxia-induced docetaxel resistance in the prostate cancer cell lines. Propofol not only decreased hypoxia-induced HIF-1α expression, but also reversed hypoxia-induced EMT by suppressing HIF-1α. Furthermore, small interfering RNA–mediated silencing of HIF-1α reversed the hypoxia-induced docetaxel resistance, although there was little change in docetaxel sensitivity between the hypoxia group and propofol group. The induction of hypoxia did not affect E-cadherin and vimentin expression, and under the siRNA knockdown conditions, the effects of propofol were obviated. These data support a role for propofol in regulating EMT in prostate cancer cells. Taken together, our findings demonstrate that propofol plays an important role in hypoxia-induced docetaxel sensitivity and EMT in prostate cancer cells and that it is a potential drug for overcoming drug resistance in prostate cancer cells via HIF-1α suppression.
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Ando, Takayuki, Ayumu Hosokawa, Kohei Ogawa, Shinya Kajiura, Yuko Itaya, Akira Ueda, Yuji Tsukioka, Takashi Kobayashi, Naoki Horikawa, and Toshiro Sugiyama. "Efficacy of weekly paclitaxel in patients with advanced gastric cancer with prior docetaxel-containing chemotherapy." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 127. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.127.
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127 Background: Efficacy of paclitaxel for docetaxel-refractory gastric cancer is not known, although partial cross-resistance between docetaxel and paclitaxel has been demonstrated in breast and ovary cancers. Therefore, we retrospectively evaluated the efficacy of paclitaxel in gastric cancer patients who had been refractory to docetaxel-containing chemotherapy. Methods: The patients who had received docetaxel-containing regimen were categorized as prior-docetaxel group, and the patients who had never received docetaxel were categorized as non-docetaxel group. Paclitaxel at 80 mg/m2 was administered by intravenous infusion in all patients, and this was repeated weekly for 3 weeks out of 4. The response rate (RR), median progression-free survival (PFS) and overall survival (OS) were evaluated in two groups. Results: 65 patients were included between April 2006 and June 2011. Among them, 26 patients were prior-docetaxel group, and 39 patients were non-docetaxel group. The median age, gender, performance status, histology, history of gastrectomy, metastatic site, and the number of metastatic sites were not statistically different between two groups. In prior-docetaxel group, the RR was 14.2% (3/21) among the patients with measurable lesions, the median PFS was 79 days (95%CI, 47-135 days), and the OS was 123 days (95% CI, 90-215 days) from the initiation of paclitaxel administration. In non-docetaxel group, the RR was 11.5% (3/26) among the patients with measurable lesions, the PFS was 82 days (95% CI, 52-106 days), and the OS was 143 days (95% CI, 121-178 days). There were no significant differences in the RR (P = 0.78), PFS (P = 0.98), and OS (P = 0.51) between two groups. Conclusions: Weekly paclitaxel was modestly active in gastric cancer patients who had been refractory to docetaxel containing chemotherapy. This represents that there was incomplete cross-resistance between docetaxel and paclitaxel in gastric cancer chemotherapy, as previously reported in other cancers.
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Bowers, Laura, Aneesha Kulkarni, and Stephen Hursting. "Obesity-Associated Leptin Signaling Promotes Chemotherapy Resistance in Basal-Like Breast Cancer: The Role of Tumor-Associated Macrophages." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 311. http://dx.doi.org/10.1093/cdn/nzaa044_010.
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Abstract Objectives Obesity is associated with a reduced response to cytotoxic chemotherapies. Given that the adipokine leptin has been shown to promote macrophage production of pro-tumor cytokines, we hypothesized that leptin-induced pro-tumor macrophage polarization is a key mediator of obesity-associated docetaxel resistance. Methods Wild-type C57BL/6 mice were fed a low-fat control (10% kcal from fat) or high-fat diet-induced obesity (DIO; 60% kcal from fat) diet for 15 weeks, then orthotopically injected with 2 mouse mammary tumor cell lines: EWnt-S (scrambled shRNA) and EWnt-L (shRNA to the leptin receptor) in the 9th and 4th mammary glands, respectively. Mice in each group were then randomized to vehicle or docetaxel (20 mg/kg/week IV for 3 weeks). The transcriptomes of both tumors (n = 6/group) were analyzed by microarray, and cell type enrichment analysis performed using the webtool xCell. The in vitro effects of leptin +/− docetaxel on macrophage polarization as well as cancer cell cytotoxicity and markers of invasive capacity are currently being assessed. Results The DIO mice had greater body weight and % body fat at euthanization versus control mice (P < 0.01 for both). Docetaxel treatment in DIO mice reduced tumor growth rate in EWnt-L tumors (P < 0.05), but not EWnt-S tumors. In contrast, docetaxel treatment reduced the EWnt-L and EWnt-S tumor growth rate in control mice (P < 0.05 for both). xCell analysis indicated that docetaxel treatment increased M2 macrophage levels in the DIO mouse tumors, but not the controls. Leptin receptor knockdown attenuated this effect. In addition, key genes related to “macrophage markers”, “cytokines and inflammatory response”, and “interleukin (IL)-6 signaling” were differentially expressed in docetaxel-treated EWnt-S tumors from DIO versus control mice. Conclusions These results indicate that leptin signaling mediates obesity-induced docetaxel resistance in the E-Wnt model of basal-like breast cancer. They also suggest that docetaxel interacts with leptin signaling to promote an increase in tumor-promoting M2 macrophages and subsequent docetaxel resistance. This hypothesis is currently being explored through our in vitro studies. Funding Sources This work was supported by a grant from the Developmental Funding Program, Lineberger Comprehensive Cancer Center, UNC Chapel Hill.
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Miyazawa, Yoshiyuki, Nobuaki Shimizu, Yutaka Takezawa, Toshiyuki Nakamura, Takeshi Miyao, Hiroshi Nakayama, Sota Kurihara, et al. "Exploratory study of prognostic factors in mCRPC patients who administered enzalutamide focusing on early PSA decline and PSA kinetics at PSA progression: Results of retrospective multicenter study." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 292. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.292.
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292 Background: Recent studies have shown that an early PSA response to AR-targeting agents in mCRPC is associated with a better prognosis. We analyzed the early PSA response to enzalutamide (ENZ) by measuring the PSA doubling time (PSADT) and PSA Velocity while monitoring oncologic outcomes and survival in Japanese patients. Methods: A total of 241 patients with mCRPC treated with ENZ were analyzed. Patients’ median age is 75±7.9 (range 53-93). The patients pre-docetaxel settings were 171 cases (71 %), post-docetaxel settings were 70 cases (29 %). The PSA-PFS and OS were assessed according to PCWG2 criteria. This study was approved by the institutional review board of Gunma University Hospital (No.1595). Results: A case where PSA did not decline at all was defined as Primary Resistance (PR). A case in which PSA once declined after treatment but then progressed was defined as Acquired Resistance (AR). Those in which PSA remained low after treatment were defined as Good Response (GR). We observed 77 PR cases (31.9 %), 125 AR cases (51.9 %) and 39 GR cases (16.2 %).PSA-PFS and OS pre-docetaxel were significantly increased as compared to patients’ post-docetaxcel (PSA-PFS; 47.0 wks vs. 13.4 wks p < 0.001, OS; Not Yet Reached vs. 80.7 wks p < 0.001). Multivariate analysis of prognostic factors, including the PSA response at 4 weeks, was performed using a Cox regression analysis. The PS (0 or 1-2), Hb (≧11.4 or < 11.4), time to CRPC(≧12 m or < 12 m), docetaxel treatment history (none or done) and a PSA decrease of 50% at 4 weeks were all significant factors for the prediction of OS (all variables, p < 0.05). In cases of acquired resistance (n = 125), a multivariate analysis using PSA kinetics factors such as PSADT and PSA Velocity (ng/mL/month) at PSA progression, Hb, time to CRPC(≧12 m or < 12 m), PSADT (≧2 months or < 2 months) and PSA Velocity ( < 20 ng/mL/month or≧20 ng/mL/month), were all factors predicting OS following PSA progression (p < 0.05). Conclusions: Our study has demonstrated that PSA dynamics after ENZ administration may be a useful prognostication factor for mCRPC patients.
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Komura, Kazumasa, Seong Ho Jeong, Kunihiko Hinohara, Fangfang Qu, Xiaodong Wang, Masayuki Hiraki, Haruhito Azuma, Gwo-Shu Mary Lee, Philip W. Kantoff, and Christopher J. Sweeney. "Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression." Proceedings of the National Academy of Sciences 113, no. 22 (May 16, 2016): 6259–64. http://dx.doi.org/10.1073/pnas.1600420113.
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The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity.
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Halder, Sushanta, Sakthivel Muniyan, Ramakanth Chirravuri-Venkata, Rama Krishna Nimmakayala, Palanisamy Nallasamy, Hareesh B. Nair, Moorthy P. Ponnusamy, Surinder K. Batra, and Parthasarathy Seshacharyulu. "Abstract 1756: Targeting LIFR/c-Myc Axis to Overcome Docetaxel Resistance in Prostate Cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 1756. http://dx.doi.org/10.1158/1538-7445.am2023-1756.
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Abstract Background: Docetaxel has been the most effective chemotherapeutic option after the emergence of Castration-resistant prostate cancer (CRPC). However, more than 50% of patients develop Docetaxel Resistance (DoceR) within three years of treatment. It also shows severe adverse effects that lead to dose reduction and treatment failure. Thus, targeting the underlying mechanism of DoceR could improve survival benefits for CRPC patients. In this study, we identified leukemia inhibitory factor receptor (LIFR) as a candidate for DoceR. We targeted it with EC914, a first-in-class oral small molecule, to overcome DoceR in CRPC. Methods: We developed three DoceR (PC3-R60, 22Rv1-R110, and LNCaP(C-83)-R50) isogeneic sub-lines by chronic Docetaxel treatment for six months. We analyzed those cell lines for drug resistance markers using RT-PCR and western blot. We evaluated the effect of EC914 in overcoming DoceR using cytotoxicity assay in Incucyte® live imaging system, colony survival assay, apoptosis induction, and cell cycle arrest using FACS analysis. RNA-seq analysis revealed molecular pathways related to EC914-mediated Docetaxel- sensitivity. In addition, we utilized RT-PCR and western blot analysis to examine EC914-responsive cancer stem cell (CSC) and LIFR/STAT pathway-related genes and proteins. Finally, we adopted human and mouse syngeneic PCa cells and patient-derived xenograft models to test the in vivo efficacy of EC914 in combination with Docetaxel. Results: LIFR showed significantly high mRNA and protein expression in Docetaxel resistant PCa cell model. EC914 combined with Docetaxel reduced considerably in vitro tumorigenicity (proliferation (p<0 01), colony growth (p<0 01)), induced apoptosis (p<0 01), and arrested cells in the G2/M and S phase (p<0 01) of the cell cycle. The combination also affected the CSC population and markers expression in DoceR PCa cells. Expression of cleaved caspase 3, caspase 9, and PARP-1 further validated apoptosis induction. Global transcriptome analysis identified EC914 treatment targets c-Myc pathway enrichment. Specifically, we found sixteen c-Myc pathway-related genes downregulated significantly (p<0 05) in transcriptomic and qRT-PCR validation. Knockdown of LIFR reduces phospho-STAT3 and phospho c-Myc without altering total STAT and c-Myc proteins. Mice subcutaneous implantation of human (p<0 05) and mouse (p<0 05) syngeneic PCa cells and patient-derived tissue (p=0 003) reduced xenograft tumor growth upon treatment with EC914 combined with Docetaxel. Conclusion: For the first time, we identified c-Myc pathway genes as potential LIFR signaling targets to overcome docetaxel resistance. Our findings support a new role and mechanism(s) of LIFR in CRPC and could inhibit MYC-addicted tumors. Citation Format: Sushanta Halder, Sakthivel Muniyan, Ramakanth Chirravuri-Venkata, Rama Krishna Nimmakayala, Palanisamy Nallasamy, Hareesh B. Nair, Moorthy P Ponnusamy, Surinder K. Batra, Parthasarathy Seshacharyulu. Targeting LIFR/c-Myc Axis to Overcome Docetaxel Resistance in Prostate Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1756.
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Glynn, Sharon A., Aidan Toner, Joe Lewis, Frank Sullivan, Laura Breen, Martin Clynes, and Francis J. Giles. "Prostate cancer inhibitory activity of a novel dual inhibitor, EL102, in combination with docetaxel, and its effects on MDR1-mediated drug resistance in vitro." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e15126-e15126. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e15126.
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e15126 Background: EL102 is a dual-action drug promoting apoptosis and inhibiting angiogenesis. It exerts its action though the inhibition of Hif1a induced hypoxic signalling and induction of the Caspase 3/7 apoptotic cascade. The drug has equal activity in normoxia and hypoxia indicating it may be equally active in these different tumor compartments. We tested its ability to circumvent chemotherapeutic drug resistance. Methods: We assessed the ability of EL102 to inhibit prostate cancer cell proliferation and motility in vitro, calculating IC50s for CWR22, 22Rv2, PC3 and DU145 prostate cancer cell lines, comparing sensitivity between androgen dependent, androgen independent and metastatic prostate cancer. Additionally we assessed the activity of EL102 in combination with docetaxel in vitro and in murine CWR22 xenografts. The ability to overcome MDR1 and BCRP mediated drug resistance was also tested using DLKP drug resistant variants which exhibit 200 fold resistance to doxorubicin, docetaxel, paclitaxel and vincristine. Results: We found that prostate cancer cell lines are sensitive to EL102 with IC50s in the region of 10-50nM. Of particular interest was the identical sensitivity of the androgen independent 22Rv1 and its androgen dependent parent CWR22, suggesting ability to overcome hormone refractory prostate cancer. Additionally we demonstrate dose response for inhibition of cell motility in metastatic DU145. In CWR22 murine mouse models treatment with EL102 resulted in decreased tumor volume compared to control. A docetaxel and EL102 combination arm demonstrated the greater inhibition of tumor growth than EL102 or docetaxel alone. The lung cancer cell line DLKP, its drug resistant variants DLKPA (MDR1 overexpressing) and DLKPMitox (BCRP overexpressing) were equally sensitive to EL102 indicating that EL102 is not a substrate for MDR1 or BCRP. Conclusions: EL102 is a potential therapeutic for the treatment of prostate cancer, in particular in combination with docetaxel, and exhbibits the potential to overcome drug resistane. Future studies will include the efficacy of this drug in prostate cancer metastatic mouse models.
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Ding, Adeline B., Erika Heninger, Shannon R. Reese, Cristina Sanchez-de-Diego, Ravi C. Yada, Nan Sethakorn, Sheena C. Kerr, et al. "Abstract 635: Osteoclasts mediate chemotherapy resistance in a fully humanized microphysiologic system of prostate cancer bone metastases." Cancer Research 84, no. 6_Supplement (March 22, 2024): 635. http://dx.doi.org/10.1158/1538-7445.am2024-635.
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Abstract Bone metastases (BM) are the most common sites of metastases in prostate cancer, occurring in ~85% of patients. Overall survival of men with castrate resistant prostate cancer with BM is less than 24 months. Docetaxel is the most commonly used therapy for patients with prostate cancer, but the response rate is only 30-40% and median duration of response is less than 9 months. Non-tumor components of the Tumor Microenvironment (TME) have been proposed to mediate treatment resistance, but few pre-clinical models capture the complex physiology of the human bone TME. We report the development of a bone TME using a humanized microphysiologic system to address this need. The LumeNEXT platform is a microphysiologic system that allows the 3-dimensional (3D) reconstitution and integrated analysis of a bone-specific TME microenvironment with functional microvasculature that traverses the chip and can be used to mimic drug delivery in patients. Primary human osteoclasts (OC) were differentiated from patient peripheral blood monocytes. LNCaP prostate cancer spheroids were grown in hanging droplets. We performed co-culture of OCs with 3D LNCaP spheroids and evaluated the efficacy of docetaxel-induced tumor cell killing in the presence of bone cells. OCs and PC spheroids were seeded into LumeNEXT devices in a collagen-based matrix and treated with 20 nM Docetaxel or DMSO vehicle for 48 hours. Docetaxel response was assessed using confocal microscopy for single spheroid diameter and cytotoxicity was measured using fluorescent cell death markers. Docetaxel-mediated killing of tumor spheroids was found to be significantly attenuated in the presence of OCs. In LNCaP only conditions, average Docetaxel-mediated cell death was 68.82%, compared to 53.86% in the LNCaP and OC co-culture condition (p<0.0001). Furthermore, Docetaxel treatment resulted in reduced tumor spheroid diameter compared to DMSO control when prostate cancer spheroids were cultured alone (p=0.0118). Additionally, the presence of OCs attenuated Docetaxel-induced morphological changes. Our data suggest that osteoclasts play a significant role in mediating chemotherapy response in prostate cancer. Future studies will examine transcriptional changes in prostate cancer cells that may be associated with Docetaxel resistance in the bone microenvironment and identify mechanisms of BM microenvironment-mediated drug resistance. Bioinformatic analysis of patient sequencing datasets is ongoing to identify osteoclast-associated signatures of treatment resistance. Citation Format: Adeline B. Ding, Erika Heninger, Shannon R. Reese, Cristina Sanchez-de-Diego, Ravi C. Yada, Nan Sethakorn, Sheena C. Kerr, Xavier T. Hazelberg, Marina N. Sharifi, David J. Beebe, Joshua M. Lang. Osteoclasts mediate chemotherapy resistance in a fully humanized microphysiologic system of prostate cancer bone metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 635.
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Thangaretnam, Krishnapriya, Islam MD Obaidul, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, and Zheng Chen. "Abstract 375: Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal adenocarcinoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 375. http://dx.doi.org/10.1158/1538-7445.am2023-375.
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Abstract Esophageal Adenocarcinoma (EAC) is the most common subtype of Esophageal Cancer in Western countries, and its incidence rate has increased over the past few decades. The overall five-year survival rate of EAC is less than 20%. Smoking is a major risk factor for EAC development. WEE1 kinase plays a crucial role in the cell cycle by regulating the G2/M checkpoint, providing a time frame for the cells to repair DNA damage. Thus, targeting WEE1 using an inhibitor could potentiate the effect of chemotherapeutic drugs. This study investigated how smoking induces WEE1 protein expression, promoting docetaxel resistance in EAC. IHC staining for WEE1 in the normal esophagus and EAC tissue sections revealed significant over-expression of WEE1 protein in EAC. Nicotine, Nicotine derived Nitrosamine Ketone (NNK), and 2% cigarette smoke extract (CSE) treatment induced WEE1 expression with a concomitant increase in CDC2 phosphorylation (p-CDC2, Y15), a well-established read-out of WEE1 activity in EAC cells. In addition, we found that smoking upregulates WEE1 expression by decreasing miR-195-5p expression levels in EAC. Based on the differential gene expression signatures in EAC cell lines FLO1 and OE33 following WEE1 knockdown, drug and small molecule induced gene expression signatures analysis, L1000 fireworks display (L1000FWD), predicted that docetaxel is one of the best drug candidates which can synergize with the WEE1 inhibitor MK1775. Smoking-induced docetaxel resistance in EAC cells measured by cell viability assay. Down-regulating WEE1 expression with siRNA or pharmacological inhibition using MK1775 significantly sensitized EAC cells to docetaxel treatment, as evidenced by a remarkable decrease in the IC50 value of docetaxel. Inhibition of WEE1 combined with docetaxel can be considered an ideal therapeutic strategy due to its superior anti-tumor efficacy compared to the standard single-agent treatment. In conclusion, our data provide a firm rationale for the clinical combination of docetaxel with MK1775 in EAC patients. Citation Format: Krishnapriya Thangaretnam, Islam MD Obaidul, Heng Lu, Dunfa Peng, Nadeem Sidiq Bhat, Mohammed Soutto, Zheng Chen. Smoking induces Wee1 expression through miRNA deregulation, promoting docetaxel resistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 375.
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Deshmukh, Chetan Dilip, Ganesh Divekar, Minish Mahendra Jain, Shailesh Arjun Bondarde, and Niraj Bhatt. "Pharmacologic differences in taxanes leading to difference in clinical activity and toxicity." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13567-e13567. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13567.
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e13567 Background: Paclitaxel and docetaxel share major parts of their structures and mechanism of action, but differ in several aspects. Both paclitaxel and docetaxel act at microtubule causing tubulin polymer generation but exhibit pharmacodynamic differences. These pharmacological differences may account for the differences observed between taxanes in their clinical activity and toxicity. Methods: Review of articles providing details of taxane pharmacology was conducted to evaluate pharmacological basis. Results: Greater uptake and slower efflux of docetaxel from tumor cells leads to longer retention time; whereas equal uptake and efflux of paclitaxel shorter retention time for paclitaxel. Hence, apoptotic and mitotic responses of paclitaxel is complete within 4 days implying that more frequent (weekly) administration of paclitaxel will be superior. High affinity to β-tubulin with docetaxel (1.9) than with paclitaxel (1.0) allows higher inhibition of tumor growth. Secondly, drug concentration causing maximum polymerization is 0.2 µM and 0.4 µM for docetaxel and paclitaxel, respectively; indicating that docetaxel is twice as potent as paclitaxel in causing microtubule polymerization. Docetaxel arrests cells in the radiosensitive G2/M phase of the cell cycle making it a potent radiosensetizer than paclitaxel. Mechanisms consistent with allosteric modulation of the reductases increase doxorubicinol formation at clinically relevant concentrations of paclitaxel when it is administered with doxorubicin. Enhanced formation of doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity causes higher cardiotoxicty when doxorubicin is administered with paclitaxel than with docetaxel. Non linear pharmacokinetics and hypersensitivity with paclitaxel and fluid retention with docetaxel is attributed to excepient of the drug rather than drug itself. Conclusions: Influx and efflux mechanism support superior weekly administration of Paclitaxel. Pharmacological differences between taxanes justify the incomplete resistance seen between taxanes. The incomplete cross resistance is specifically related to docetaxelactivity in paclitaxel resistant cases.
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Li, Jia, Jing Ke, Cheng-lin Qin, and Xun Zhu. "LINC00680 modulates docetaxel resistance in breast cancer via the miR-320b/CDKL5 axis." International Journal of Immunopathology and Pharmacology 36 (January 2022): 039463202211056. http://dx.doi.org/10.1177/03946320221105608.
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Introduction: Increasing evidence has indicated that LINC00680 represents an oncogenic factor in cancer; however, the mechanism by which LINC00680 contributes to breast cancer (BC) remains unknown. Methods: A dual-luciferase reporter assay was used to explore the relationship between LINC00680, miR-320b, and cyclin-dependent kinase 5 (CDKL5). A CCK-8 assay and transwell assay were utilized to evaluate the proliferation and invasion in docetaxel-resistant BC cells, respectively. Results: LINC00680 and CDKL5 protein levels were both upregulated when induced by different concentrations of docetaxel. LINC00680 knockdown decreased the expression level of drug resistance-related genes, proliferation, and invasion of BC cells. Bioinformatics prediction and dual-luciferase assays revealed that miR-320b targeted the 3′-unstranslated regions (UTR) of both LINC00680 and CDKL5, suggesting that the modulation of LINC00680 on CDKL5 occurred via sequestering miR-320b. Conclusion: Overall, this study highlights the important role of LINC00680 in docetaxel resistance through the miR-320b/CDKL5 pathway and provides a novel therapeutic strategy for BC drug resistance.
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Thomson, Alastair, Adam Pollard, and Frances May Mark. "Timing of docetaxel chemotherapy and impact on outcomes in metastatic castrate-resistant prostate cancer (MCRPC)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 298. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.298.
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298 Background: Docetaxel use has led to a significant prolongation in overall survival (OS) in metastatic prostate cancer after castrate resistance, with a more substantial OS gain when used in combination with initial androgen deprivation therapy (ADT). There is however limited information on outcomes in patients who initially do not receive chemotherapy, perhaps through patient choice or impaired performance status, who become suitable for docetaxel, comparing earlier with later docetaxel treatment. Methods: We retrospectively reviewed patients’ electronic clinical and prescribing records diagnosed with MCRPC and treated with docetaxel from 01/01/2006 to 24/11/2016 in a single centre in the UK. Data was reviewed for number of individual treatments received pre and post chemotherapy, including initial ADT, enzalutamide, abiraterone, docetaxel, cabazitaxel, mitoxantrone, radium 223, single agent steroids and diethylstilboestrol. Prostate specific antigen (PSA) response, number of cycles and dosing of docetaxel and OS were also reviewed. Results: 168 consecutive patients with MCRPC receiving docetaxel were reviewed. Median Gleason grade across the three groups was 8. 48 patients (29%) received docetaxel after 1 or 2 previous treatments, 105 (63%) after 3 or 4 previous treatments and 15 (9%) after 5 or 6. PSA response rates were superior in the earlier treated group (61%, p=0.003), compared with 30% and 31% respectively in the later groups. Median number of cycles was 5.5 overall, with a mean weighted dose received of 396mg/m2, 373mg/m2 and 301mg/m2 in the after 1 or 2 treatments, after 3 or 4 treatments and after 5 or 6 treatment groups. Median OS from castrate resistance for the earlier group was 29 months, not significantly less (p=0.1) than the 35 months for an intermediate number of prior treatments and 42 months for the later treated group. Conclusions: In this group of patients in routine clinical practice who do not receive docetaxel with initial ADT, PSA response rates are significantly improved and overall dose received is higher with subsequent earlier use. However, overall survival is not significantly different between the early and later docetaxel treated patients.
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Mukherji, Deborah, Carmel Jo Pezaro, Diletta Bianchini, Andrea Zivi, and Johann Sebastian De Bono. "Response to abiraterone acetate in the postchemotherapy setting in patients with castration-resistant prostate cancer whose disease progresses early on docetaxel." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 17. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.17.
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17 Background: Abiraterone acetate (AA) has recently been approved for men with metastatic castration-resistant prostate cancer (CRPC) following docetaxel chemotherapy. AA inhibits CYP17, reducing androgen production and thereby impacting androgen receptor (AR) signalling. Recent evidence suggests taxanes also impact AR signalling, raising concerns about potential cross-resistance. We have previously shown that docetaxel has no antitumor activity in AA refractory patients. We have now evaluated the antitumor activity of AA post-docetaxel to determine the activity of AA in docetaxel refractory patients. Methods: Forty four men with CRPC treated with docetaxel (75 mg/m2 every 21 days) followed by post-chemotherapy AA at the Royal Marsden Hospital were identified. Radiological response by RECIST, PSA response by PSAWG2 criteria and symptomatic benefit were evaluated. Results: An average of 9 cycles of docetaxel were given (range 3-17); 7 patients discontinued chemotherapy due to progression of disease and 10 for toxicity. Of 40 patients with PSA data available, 26 (65%) had a PSA decline of at least 50%. At commencement of AA, median age was 68 years. Bone, nodal and visceral metastases were present in 38 (86%), 23 (52%) and 6 (14%) of the cohort respectively. An average of 5 months of treatment were delivered and 23 patients continue on AA. Of the 44, 7 (16%) patients had a 50% or greater PSA decline on AA. None of the 7 patients who were docetaxel refractory had a subsequent PSA, radiological or clinical response to AA. Of the 6 patients who received less than 5 cycles of docetaxel due to toxicity, 2 had subsequent PSA response on AA. There was no relationship between length of time on LHRH agonist and PSA response to AA. Conclusions: Our data suggest that patients who are refractory to docetaxel do not respond to AA. Overall, in conjunction with our other evidence that in AA-refractory patients docetaxel has no antitumor activity, these data provide further evidence for cross-resistance between these two agents.
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Ning, Yang-min, William D. Figg, and William L. Dahut. "Reversal of Docetaxel Resistance With Bevacizumab and Thalidomide." Clinical Genitourinary Cancer 7, no. 2 (August 2009): E37—E38. http://dx.doi.org/10.3816/cgc.2009.n.020.
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Honma, Kimi, Kyoko Iwao-Koizumi, Fumitaka Takeshita, Yusuke Yamamoto, Teruhiko Yoshida, Kazuto Nishio, Shunji Nagahara, Kikuya Kato, and Takahiro Ochiya. "RPN2 gene confers docetaxel resistance in breast cancer." Nature Medicine 14, no. 9 (August 17, 2008): 939–48. http://dx.doi.org/10.1038/nm.1858.
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Ganju, Aditya, Murali M. Yallapu, Sheema Khan, Stephen W. Behrman, Subhash C. Chauhan, and Meena Jaggi. "Nanoways to overcome docetaxel resistance in prostate cancer." Drug Resistance Updates 17, no. 1-2 (April 2014): 13–23. http://dx.doi.org/10.1016/j.drup.2014.04.001.
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Scherbakov, Alexander M., Anna A. Basharina, Danila V. Sorokin, Ekaterina I. Mikhaevich, Iman E. Mizaeva, Alexandra L. Mikhaylova, Tatiana A. Bogush, and Mikhail A. Krasil’nikov. "Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance." Cancer Drug Resistance 6, no. 1 (2023): 103–15. http://dx.doi.org/10.20517/cdr.2022.96.
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Aim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. Methods: The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. Results: The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (P < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC50 value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (P < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. Conclusion: Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.
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van Soest, Robert J., Martin E. van Royen, Ellen S. de Morrée, Erik A. C. Wiemer, Ron H. J. Mathijssen, Ronald De Wit, and Wytske M. van Weerden. "Effects on androgen receptor nuclear import by docetaxel, cabazitaxel, abiraterone, and enzalutamide: Potential mechanism for cross-resistance in castration-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 5064. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.5064.
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5064 Background: Recent reports have suggested that paclitaxel and docetaxel, which exert their therapeutic activity primarily through inhibition of microtubule function and mitosis, also impair androgen receptor (AR) signaling. AR signaling is the key therapeutic target for the newly available agents abiraterone and enzalutamide. A recent study suggested impaired efficacy of docetaxel when given after progression on abiraterone in patients with CRPC. To identify potential mechanisms of cross-resistance, we investigated whether and to what extent AR nuclear translocation is affected by docetaxel, cabazitaxel, abiraterone and enzalutamide. Methods: Hep3B cells stably expressing GFP labeled AR were used for AR translocation studies. Cells were seeded on a cover slip in steroid-stripped medium (DCC) and treated with docetaxel (1 µM), cabazitaxel (1 µM), abiraterone (6 µM) and enzalutamide (1 µM). The anthracenedione mitoxantrone (100 nM) that does not target the microtubule cytoskeleton was used as a control cytotoxic agent. Following incubation for 48 hours, the synthetic androgen R1881 was added to study dynamics of AR nuclear import by time-lapse confocal microscopy. Results: Docetaxel and cabazitaxel inhibited R1881 induced AR nuclear translocation with 21% and 34% respectively compared to control, while mitoxantrone did not affect AR transport. Abiraterone inhibited AR translocation with 58% and enzalutamide completely blocked AR translocation. Conclusions: These data point towards a role for microtubules in AR nuclear transport and an additional mechanism of taxane activity in CRPC. Docetaxel, cabazitaxel, abiraterone and enzalutamide all interfere with AR nuclear transport, which is a crucial step in AR signaling. Our findings identify and provide insight in a potential mechanism of clinical cross-resistance between the two taxanes currently registered for treatment in CRPC and the novel agents abiraterone and enzalutamide. Further investigations are warranted in order to define if this potential cross-resistance impacts the most suitable treatment sequence for these drugs in CRPC.
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Haldar, Subhash, Rajeev Mishra, Sandrine Billet, Manish Thiruvalluvan, Veronica R. Placencio-Hickok, Anisha Madhav, Frank Duong, et al. "Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance." Proceedings of the National Academy of Sciences 117, no. 15 (April 1, 2020): 8515–23. http://dx.doi.org/10.1073/pnas.1910952117.
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Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity.
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Pudova, Elena, Anastasiya Kobelyatskaya, Irina Katunina, Anastasiya Snezhkina, Kirill Nyushko, Maria Fedorova, Vladislav Pavlov, et al. "Docetaxel Resistance in Castration-Resistant Prostate Cancer: Transcriptomic Determinants and the Effect of Inhibiting Wnt/β-Catenin Signaling by XAV939." International Journal of Molecular Sciences 23, no. 21 (October 25, 2022): 12837. http://dx.doi.org/10.3390/ijms232112837.
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Castration-resistant prostate cancer (CRPC) is a common form of prostate cancer in which docetaxel-based chemotherapy is used as the first line. The present study is devoted to the analysis of transcriptome profiles of tumor cells in the development of resistance to docetaxel as well as to the assessment of the combined effect with the XAV939 tankyrase inhibitor on maintaining the sensitivity of tumor cells to chemotherapy. RNA-Seq was performed for experimental PC3 cell lines as well as for plasma exosome samples from patients with CRPC. We have identified key biological processes and identified a signature based on the expression of 17 mRNA isoforms associated with the development of docetaxel resistance in PC3 cells. Transcripts were found in exosome samples, the increased expression of which was associated with the onset of progression of CRPC during therapy. The suppression of pathways associated with the participation of cellular microtubules has also been shown when cells are treated with docetaxel in the presence of XAV939. These results highlight the importance of further research into XAV939 as a therapeutic agent in the treatment of CRPC; moreover, we have proposed a number of mRNA isoforms with high predictive potential, which can be considered as promising markers of response to docetaxel.
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Pouptsis, Athanasios, Styliani Germanou, Nick Waldron, Thomas Young, Madeha Khan, Simon Hughes, Debra Hannah Josephs, Sarah Maria Rudman, Deborah Enting, and Simon Chowdhury. "Primary resistance in docetaxel and androgen deprivation therapy in metastatic castrate sensitive prostate cancer patients." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 342. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.342.
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342 Background: Docetaxel chemotherapy combined with androgen deprivation therapy (ADT) has become the new standard of care in patients with metastatic castrate sensitive prostate cancer as it has shown significant benefit in terms of overall survival (OS) and response rates (Sweeney 2015, James 2016). However a subgroup of patients still experience early progression. Methods: We searched the hospital database for patients treated with docetaxel in the castrate sensitive setting. Eligible patients included those with newly diagnosed metastatic prostate adenocarcinoma and also patients with relapsed metastatic disease post radical radiotherapy or radical prostatectomy. Patients starting chemotherapy > 12 weeks after commencing ADT were excluded. Results: We identified 72 patients treated with docetaxel and ADT between August 2014 and September 2017. The median age was 66 years (49-84 years). Of the 72 patients, 63 (88%) had bone metastases, 5 (7%) had visceral metastases and 45 (63%) had pelvic lymph node disease. Seven patients (9.7%) had relapsed metastatic disease post radical treatment. All patients had ≤6 cycles of docetaxel. Median time from diagnosis of metastatic disease to commencing castrate resistant treatment was 13 months (2-41 months). Median duration of follow-up was 16 months (5-39 months). Six patients (8%) had biochemical, radiological or clinical progression during, or at completion of docetaxel chemotherapy. One patient terminated treatment before completion of six cycles due to disease progression. The median presenting PSA in this group was 49.5 ug/L (9.04-2290 ug/L) and 2 patients had visceral disease. Of these 6 patients, 2 have died, and the median OS for the group was 11.5 months (8-22 months). Five patients were subsequently treated with enzalutamide and 1 with abiraterone. Conclusions: Despite the improvement in OS and response rates with the use of early docetaxel, a clinically significant number of patients developed disease progression during treatment, and these patients have a particularly poor prognosis. These patients should be the focus of future clinical trials.
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Rushworth, Linda K., Victoria Harle, Peter Repiscak, William Clark, Robin Shaw, Holly Hall, Martin Bushell, Hing Y. Leung, and Rachana Patel. "In vivo CRISPR/Cas9 knockout screen: TCEAL1 silencing enhances docetaxel efficacy in prostate cancer." Life Science Alliance 3, no. 12 (October 8, 2020): e202000770. http://dx.doi.org/10.26508/lsa.202000770.
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Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may enhance the efficacy of docetaxel, with transcription elongation factor A–like 1 (Tceal1) as the top candidate. TCEAL1 function is not fully characterised; it may modulate transcription in a promoter dependent fashion. Suppressed TCEAL1 expression in multiple human prostate cancer cell lines enhanced therapeutic response to docetaxel. Based on gene set enrichment analysis from transcriptomic data and flow cytometry, we confirmed that loss of TCEAL1 in combination with docetaxel leads to an altered cell cycle profile compared with docetaxel alone, with increased subG1 cell death and increased polyploidy. Here, we report the first in vivo genome-wide treatment sensitisation CRISPR screen in prostate cancer, and present proof of concept data on TCEAL1 as a candidate for a combinational strategy with the use of docetaxel.
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Noaman, Ali Sedeeq, and Ercan Caca. "Role of Gene Expression Profiling in Colorectal Cancer by Using Docetaxel and Lapatinib." INTERNATIONAL JOURNAL OF PHARMACEUTICAL QUALITY ASSURANCE 15, no. 03 (September 25, 2024): 1607–12. http://dx.doi.org/10.25258/ijpqa.15.3.77.
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Aim: 1-Determine cell viability by using docetaxel and lapatinib. 2-Determine the effect of the clinically relevant drugs on the regulation genes. Methods: We employed MTT assays to evaluate the cell viability of three colorectal cancer cell lines (HT-29, HCT-116, and SW-620) following treatment with docetaxel and lapatinib. Subsequently, RNA was isolated from both treated and untreated HT-29 and HCT-116 cells. HT-29 cells were exposed to 3.9uM lapatinib and 0.027uM docetaxel, while HCT-116 cells were treated with 5.6uM lapatinib and 0.038uM docetaxel. The concentrations used were based on the IC50 values for docetaxel and lapatinib in HT-29 and HCT-116 cells. Real-time PCR analysis was conducted to confirm data. Results: The results of MTT assays demonstrated a decrease in cell viability for HT29, HCT-116, and SW-620 cells as the concentrations of docetaxel and lapatinib increased. This indicates the effectiveness of both drugs in reducing the viability of these colorectal cancer cell lines. In addition, the gene expression analysis revealed that docetaxel and lapatinib had notable effects on the genetic activity of these cells. Specifically, these drugs down-regulated genes that play crucial roles in cell proliferation, cell cycle progression, transcription factors, cell signaling, and oncogenesis. On the positive side, there was an up-regulation of genes related to inducing apoptosis, causing cell cycle arrest, and promoting cellular differentiation in all three cell lines. However, a potential concern emerged as docetaxel and lapatinib also up-regulated genes associated with chemotherapeutic resistance. This suggests a potential challenge in the form of induced resistance to these drugs by the cancer cells. Conclusions: Docetaxel and lapatinib altered numerous genes, and many of these changes may be related to the molecular processes by which these drugs inhibit the growth of colorectal cancer cells. This data may be applied to future mechanistic studies and to the development of improved therapies for colorectal cancer.
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Assoun, Sandra, Luca Campedel, Morgan Roupret, Christophe Vaessen, Jerome Parra, Haide Angele Boostandoost, Eva Comperat, et al. "Antitumor activity of abiraterone, enzalutamide, and docetaxel following treatment with diethystilbestrol in castration-resistant prostate cancer." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): e581-e581. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.e581.
Full textAbstract:
e581 Background: Docetaxel and Next-Generation Anti-Androgens (NGAA) including abiraterone and enzalutamide represent the standard of treatment for patients with castration-resistant prostate cancer (CRPC). Treatment sequencing of these agents is a challenge. Recent studies identified cross-resistances between hormonal therapies and taxanes, as well as between different NGAA. In aiming to elucidate whether synthetic oestrogen diethylstilbestrol (DES) therapy impacts the efficacy of later-line treatments or not, we evaluated the antitumor activity of NGAA and docetaxel following DES therapy in CRPC patients. Methods: All patients with CRPC treated at Pitié-Salpêtrière hospital in first-line setting with DES from September 1995 to July 2016 were retrospectively identified. We evaluated further activities of abiraterone, enzalutamide and docetaxel in those patients after DES therapy, using Prostate Cancer Working Group 3 criteria. Clinicopathologic characteristics, including age, performans status, metastatic sites at diagnosis and treatments initiation, and data survival were also assessed. Results: Twenty-three patients with CRPC were initially treated with DES with a median time to prostate-specific antigen (PSA) progression of 9.7 months (range, 4.7-20.3). Thirteen patients(56.5%) received abiraterone or enzalutamide before docetaxel and 21 patients (91.3%) after. Median age at first NGAA initiation was 79 years) range, 55-91). Only one patient (7.7%) achieved a PSA decline before docetaxel and two out of 18 evaluable patients (11.1%) after docetaxel. Median time to PSA progression and overall survival with a NGAA treatment were respectively 2.8 (range, 2.0-4.1) and 16.5 months(range, 4.3-31.0). Fifty percent of patients showed a PSA response with docetaxel. No clinical factors were found to be significantly associated with PSA response to NGAA treatment, nor to docetaxel. Conclusions: The activity of NGAA appears markedly limited after a DES therapy, regardless of the PSA response to docetaxel. These data suggest the likelihood of a cross-resistance mechanism between DES and NGAA, without no impact on taxanes pathways.