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1
Lu, Shuyan, Tae Sung, Marina Amaro, Brad Hirakawa, Bart Jessen, and Wenyue Hu. "Phenotypic Characterization of Targeted Knockdown of Cyclin-Dependent Kinases in the Intestinal Epithelial Cells." Toxicological Sciences 177, no. 1 (June 18, 2020): 226–34. http://dx.doi.org/10.1093/toxsci/kfaa092.
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Abstract Cyclin-dependent kinases (CDKs) are serine/threonine kinases that regulate cell cycle and have been vigorously pursued as druggable targets for cancer. There are over 20 members of the CDK family. Given their structural similarity, selective inhibition by small molecules has been elusive. In addition, collateral damage to highly proliferative normal cells by CDK inhibitors remains a safety concern. Intestinal epithelial cells are highly proliferative and the impact of individual CDK inhibition on intestinal cell proliferation has not been well studied. Using the rat intestinal epithelial (IEC6) cells as an in vitro model, we found that the selective CDK4/6 inhibitor palbociclib lacked potent anti-proliferative activity in IEC6 relative to the breast cancer cell line MCF7, indicating the absence of intestinal cell reliance on CDK4/6 for cell cycle progression. To further illustrate the role of CDKs in intestinal cells, we chose common targets of CDK inhibitors (CDK 1, 2, 4, 6, and 9) for targeted gene knockdown to evaluate phenotypes. Surprisingly, only CDK1 and CDK9 knockdown demonstrated profound cell death or had moderate growth effects, respectively. CDK2, 4, or 6 knockdowns, whether single, double, or triple combinations, did not have substantial impact. Studies evaluating CDK1 knockdown under various cell seeding densities indicate direct effects on viability independent of proliferation state and imply a potential noncanonical role for CDK1 in intestinal epithelial biology. This research supports the concept that CDK1 and CDK9, but not CDKs 2, 4, or 6, are essential for intestinal cell cycle progression and provides safety confidence for interphase CDK inhibition.
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Shapiro, Geoffrey I. "Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment." Journal of Clinical Oncology 24, no. 11 (April 20, 2006): 1770–83. http://dx.doi.org/10.1200/jco.2005.03.7689.
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Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G1 arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G2 phases and induces E2F transcription factor–dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short half-lives, including those encoding antiapoptosis family members, cell cycle regulators, as well as p53 and nuclear factor-kappa B–responsive gene targets. These effects may account for apoptosis induced by cdk9 inhibitors, especially in malignant hematopoietic cells, and may also potentiate cytotoxicity mediated by disruption of a variety of pathways in many transformed cell types. Current work is focusing on overcoming pharmacokinetic barriers that hindered development of flavopiridol, a pan-cdk inhibitor, as well as assessing novel classes of compounds potently targeting groups of cell cycle cdks (cdk4/6 or cdk2/1) with variable effects on the transcriptional cdks 7 and 9. These efforts will establish whether the strategy of cdk inhibition is able to produce therapeutic benefit in the majority of human tumors.
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Fassl, Anne, Christopher Brain, Monther Abu-Remaileh, Iga Stukan, Deborah Butter, Piotr Stepien, Avery S. Feit, et al. "Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition." Science Advances 6, no. 25 (June 2020): eabb2210. http://dx.doi.org/10.1126/sciadv.abb2210.
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Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor–positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.
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Baughn, Linda B., Maurizio Di Liberto, Kaida Wu, Peter Toogood, Tracey Louie, Rachel Gottschalk, Ruben Niesvizky, et al. "A Novel Orally Active Small Molecule Potently Induces G1 Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cdk4/6." Blood 108, no. 11 (November 16, 2006): 369. http://dx.doi.org/10.1182/blood.v108.11.369.369.
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Abstract Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow (BM). Inhibition of Cdk4 and Cdk6 by the Cdk inhibitor, p18(INK4c), is required for the generation of normal, functional plasma cells1. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of Cdk4-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of BM myeloma cells in vivo2. These data identify Cdk4 and Cdk6 as key determinants in the loss of cell cycle control in myeloma and suggest that Cdk4/6 may be effective targets for therapeutic intervention. Here we show that by specific inhibition of Cdk4/6, the orally active small molecule PD 0332991 potently induces G1 arrest in primary BM myeloma cells ex vivo, and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation, and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B cell cancers.
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Vilgelm, Anna E., Nabil Saleh, Rebecca Shattuck-Brandt, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chiann Chen, C. Andrew Johnson, et al. "MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21." Science Translational Medicine 11, no. 505 (August 14, 2019): eaav7171. http://dx.doi.org/10.1126/scitranslmed.aav7171.
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Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)–AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.
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Facharztmagazine, Redaktion. "Brustkrebs: CDK4/6-Inhibition punktet." Im Fokus Onkologie 23, no. 4 (September 2020): 97. http://dx.doi.org/10.1007/s15015-020-2542-8.
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Facharztmagazine, Redaktion. "CDK4/6 -Inhibition bei Brustkrebs." Im Fokus Onkologie 24, no. 3 (June 2021): 73. http://dx.doi.org/10.1007/s15015-021-3516-1.
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Facharztmagazine, Redaktion. "CDK4/6 -Inhibition bei Brustkrebs." InFo Hämatologie + Onkologie 24, no. 6 (June 2021): 68. http://dx.doi.org/10.1007/s15004-021-8712-9.
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De Dominici, Marco, Patrizia Porazzi, Youcai Xiao, Allen Chao, Hsin-Yao Tang, Gaurav Kumar, Paolo Fortina, et al. "Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs." Blood 135, no. 18 (April 30, 2020): 1560–73. http://dx.doi.org/10.1182/blood.2019003604.
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Abstract Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth, whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are, in part, kinase-independent in Ph+ ALL. Accordingly, we developed CDK4/6–targeted proteolysis-targeting chimeras (PROTACs) that inhibit CDK6 enzymatic activity in vitro, promote the rapid and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S-phase cells concomitant with inhibition of CDK6-regulated phospho-RB and FOXM1 expression. No such effects were observed in CD34+ normal hematopoietic progenitors, although CDK6 was efficiently degraded. Treatment with the CDK6-degrading PROTAC YX-2-107 markedly suppressed leukemia burden in mice injected with de novo or tyrosine kinase inhibitor–resistant primary Ph+ ALL cells, and this effect was comparable or superior to that of the CDK4/6 enzymatic inhibitor palbociclib. These studies provide “proof of principle” that targeting CDK6 with PROTACs that inhibit its enzymatic activity and promote its degradation represents an effective strategy to exploit the “CDK6 dependence” of Ph+ ALL and, perhaps, of other hematologic malignancies. Moreover, they suggest that treatment of Ph+ ALL with CDK6-selective PROTACs would spare a high proportion of normal hematopoietic progenitors, preventing the neutropenia induced by treatment with dual CDK4/6 inhibitors.
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DiRocco, Derek P., John Bisi, Patrick Roberts, Jay Strum, Kwok-Kin Wong, Norman Sharpless, and Benjamin D. Humphreys. "CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury." American Journal of Physiology-Renal Physiology 306, no. 4 (February 15, 2014): F379—F388. http://dx.doi.org/10.1152/ajprenal.00475.2013.
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Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or “pharmacological quiescence,” represents a novel strategy to prevent AKI.
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Guiley, Keelan Z., Jack W. Stevenson, Kevin Lou, Krister J. Barkovich, Vishnu Kumarasamy, Tilini U. Wijeratne, Katharine L. Bunch, et al. "p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition." Science 366, no. 6471 (December 12, 2019): eaaw2106. http://dx.doi.org/10.1126/science.aaw2106.
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The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex with cyclin D1 (CDK4-CycD1). Structural and biochemical data revealed that binding of phosphorylated p27 (phosp27) to CDK4 altered the kinase adenosine triphosphate site to promote phosphorylation of the retinoblastoma tumor suppressor protein (Rb) and other substrates. Surprisingly, purified and endogenous phosp27-CDK4-CycD1 complexes were insensitive to the CDK4-targeting drug palbociclib. Palbociclib instead primarily targeted monomeric CDK4 and CDK6 (CDK4/6) in breast tumor cells. Our data characterize phosp27-CDK4-CycD1 as an active Rb kinase that is refractory to clinically relevant CDK4/6 inhibitors.
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Swarbrick, Alexander, Christine S. L. Lee, Robert L. Sutherland, and Elizabeth A. Musgrove. "Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells." Molecular and Cellular Biology 20, no. 7 (April 1, 2000): 2581–91. http://dx.doi.org/10.1128/mcb.20.7.2581-2591.2000.
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ABSTRACT The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G1 cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27Kip1among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27Kip1 and few were bound to p21Cip1. In vitro, recombinant His6-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His6-p27 in vitro or p27Kip1 in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18INK4c and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18INK4c led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27Kip1 and p18INK4c cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor β and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation.
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Göke, R., P. Barth, A. Schmidt, B. Samans, and B. Lankat-Buttgereit. "Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21Waf1/Cip1." American Journal of Physiology-Cell Physiology 287, no. 6 (December 2004): C1541—C1546. http://dx.doi.org/10.1152/ajpcell.00025.2004.
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We show that the recently discovered tumor suppressor pdcd4 represses the transcription of the mitosis-promoting factor cyclin-dependent kinase (CDK)1/cdc2 via upregulation of p21Waf1/Cip1. p21Waf1/Cip1 inhibits CDK4/6 and CDK2. Decrease of CDK4/6 and CDK2 enhances the binding of pRb to E2F/DP, which in turn together bind to and repress the cdc2 promoter. Upregulation of CDK1/cdc2 accompanied by a malignant change was previously reported in colon cancer. We show that expression of pdcd4 as an indirect suppressor of CDK1/cdc2 is lost in progressed carcinomas of lung, breast, colon, and prostate. Furthermore, it seems that localization and expression of pdcd4 directly correlate with tumor progression. Finally, the CDK1/cdc2 inhibitor roscovitine reduces the proliferation of several tumor cell lines, suggesting that inhibition of CDK1/cdc2 may be a useful strategy against malignant transformation. Therefore, pdcd4 might serve as a novel target for antineoplastic therapies.
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Feng, Rentian, Xiangao Huang, G. David Roodman, Selina Chen-Kiang, and Suzanne Lentzsch. "Inhibition of Cdk4/6 by PD 0332991 Results in Abrogation of Osteoclast Formation." Blood 112, no. 11 (November 16, 2008): 3676. http://dx.doi.org/10.1182/blood.v112.11.3676.3676.
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Abstract Multiple myeloma (MM) is characterized by increased osteoclast activity resulting in bone destruction and development of lytic lesions. Despite overall survival achieved by new treatment modalities, new drugs are required to specifically and effectively inhibit bone destruction. PD 0332991 is a selective small molecule inhibitor of cyclin-dependent kinase (Cdk)4 and Cdk6 with oral bioavailability. We have demonstrated recently that inhibition of Cdk4/6 by PD 0332991 effectively controls MM tumor expansion in animal models and sensitizes chemoresistant MM tumor cells to bortezomib killing despite protection by bone marrow stromal cells. Currently clinical phase I/II trials are ongoing to test the efficacy of the combination of PD 0332991 and bortezomib. Selective inhibition of Cdk4/6 by PD 0332991 leads to sustained G1 arrest but not apoptosis, and this appears to be cell type-specific. Consistent with these findings, PD 0332991 is well tolerated in MM patients. On this basis, we address the possibility that PD 0332991, alone and in combination with bortezomib, may inhibit osteoclastogenesis, by culturing non-adherent mononuclear bone marrow cells from MM patients cultured in the presence of M-CSF and RANKL for three weeks. Treatment of human osteoclast cultures with PD 0332991 for 3 weeks decreased osteoclast formation in a dose-dependent manner with an IC50 50 nM. The combination of PD 0332991 and bortezomib led to synergistic inhibition of osteoclast formation and completely abrogated osteoclastogenesis with low dose PD 0332991 (25 nM) and bortezomib (2 nM). Furthermore, we show in a time course study that treatment with PD 0332991 for the first week, but not the second or third week, was sufficient to inhibit osteoclast formation. PD 0332991 is the only known selective inhibitor of Cdk4 and Cdk6, which at concentration below 5 uM does not cross react with at least 38 kinases or induce apoptosis. Taken together, our data suggest that by inducing G1 arrest and inhibiting progenitor expansion, PD 0332991 is a powerful and selective inhibitor for osteoclastogenesis. We propose that targeting Cdk4/6 with PD 0332291 in combination therapy is a promising therapeutic strategy to improve bone integrity in MM.
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Choi, Yoon Jong, and Piotr Sicinski. "Unexpected Outcomes of CDK4/6 Inhibition." Oncotarget 4, no. 2 (February 27, 2013): 176–77. http://dx.doi.org/10.18632/oncotarget.912.
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Knudsen, Erik S., and Agnieszka K. Witkiewicz. "The transcriptome of CDK4/6 inhibition." Aging 9, no. 8 (August 30, 2017): 1859–60. http://dx.doi.org/10.18632/aging.101285.
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Dall’Acqua, Alessandra, Michele Bartoletti, Nastaran Masoudi-Khoram, Roberto Sorio, Fabio Puglisi, Barbara Belletti, and Gustavo Baldassarre. "Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives." Cancers 13, no. 12 (June 17, 2021): 3035. http://dx.doi.org/10.3390/cancers13123035.
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Alterations in components of the cell-cycle machinery are present in essentially all tumor types. In particular, molecular alterations resulting in dysregulation of the G1 to S phase transition have been observed in almost all human tumors, including ovarian cancer. These alterations have been identified as potential therapeutic targets in several cancer types, thereby stimulating the development of small molecule inhibitors of the cyclin dependent kinases. Among these, CDK4 and CDK6 inhibitors confirmed in clinical trials that CDKs might indeed represent valid therapeutic targets in, at least some, types of cancer. CDK4 and CDK6 inhibitors are now used in clinic for the treatment of patients with estrogen receptor positive metastatic breast cancer and their clinical use is being tested in many other cancer types, alone or in combination with other agents. Here, we review the role of CDK4 and CDK6 complexes in ovarian cancer and propose the possible use of their inhibitors in the treatment of ovarian cancer patients with different types and stages of disease.
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Wright, Gabriela M., Nick T. Gimbrone, Bhaswati Sarcar, Trent R. Percy, Edna R. Gordián, Fumi Kinose, Natália J. Sumi, Uwe Rix, and W. Douglas Cress. "CDK4/6 inhibition synergizes with inhibition of P21-Activated Kinases (PAKs) in lung cancer cell lines." PLOS ONE 16, no. 6 (June 17, 2021): e0252927. http://dx.doi.org/10.1371/journal.pone.0252927.
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Theoretically, small molecule CDK4/6 inhibitors (CDK4/6is) represent a logical therapeutic option in non-small cell lung cancers since most of these malignancies have wildtype RB, the key target of CDKs and master regulator of the cell cycle. Unfortunately, CDK4/6is are found to have limited clinical activity as single agents in non-small cell lung cancer. To address this problem and to identify effective CDK4/6i combinations, we screened a library of targeted agents for efficacy in four non-small cell lung cancer lines treated with CDK4/6 inhibitors Palbociclib or Abemaciclib. The pan-PAK (p21-activated kinase) inhibitor PF03758309 emerged as a promising candidate with viability ratios indicating synergy in all 4 cell lines and for both CDK4/6is. It is noteworthy that the PAKs are downstream effectors of small GTPases Rac1 and Cdc42 and are overexpressed in a wide variety of cancers. Individually the compounds primarily induced cell cycle arrest; however, the synergistic combination induced apoptosis, accounting for the synergy. Surprisingly, while the pan-PAK inhibitor PF03758309 synergizes with CDK4/6is, no synergy occurs with group I PAK inhibitors FRAX486 or FRAX597. Cell lines treated only with Ribociclib, FRAX486 or FRAX597 underwent G1/G0 arrest, whereas combination treatment with these compounds predominantly resulted in autophagy. Combining high concentrations of FRAX486, which weakly inhibits PAK4, and Ribociclib, mimics the autophagy and apoptotic effect of PF03758309 combined with Ribociclib. FRAX597, a PAKi that does not inhibit PAK4 did not reduce autophagy in combination with Ribociclib. Our results suggest that a unique combination of PAKs plays a crucial role in the synergy of PAK inhibitors with CDK4/6i. Targeting this unique PAK combination, could greatly improve the efficacy of CDK4/6i and broaden the spectrum of cancer treatment.
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Wang, Lisheng, Jie Wang, Bradley W. Blaser, Anne-Marie Duchemin, Donna F. Kusewitt, Tom Liu, Michael A. Caligiuri, and Roger Briesewitz. "Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia." Blood 110, no. 6 (September 15, 2007): 2075–83. http://dx.doi.org/10.1182/blood-2007-02-071266.
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Abstract Entry into the cell cycle is mediated by cyclin-dependent kinase 4/6 (CDK4/6) activation, followed by CDK2 activation. We found that pharmacologic inhibition of the Flt3 internal tandem duplication (ITD), a mutated receptor tyrosine kinase commonly found in patients with acute myelogenous leukemia (AML), led to the down-regulation of cyclin D2 and D3 followed by retinoblastoma protein (pRb) dephosphorylation and G1 cell-cycle arrest. This implicated the D-cyclin-CDK4/6 complex as a downstream effector of Flt3 ITD signaling. Indeed, single-agent PD0332991, a selective CDK4/6 inhibitor, caused sustained cell-cycle arrest in Flt3 ITD AML cell lines and prolonged survival in an in vivo model of Flt3 ITD AML. PD0332991 caused an initial cell-cycle arrest in well-established Flt3 wild-type (wt) AML cell lines, but this was overcome by down-regulation of p27Kip and reactivation of CDK2. This acquired resistance was not observed in a Flt3 ITD and a Flt3 wt sample from a patient with primary AML. In summary, the mechanism of cell-cycle arrest after treatment of Flt3 ITD AML with a Flt3 inhibitor involves down-regulation of cyclin D2 and D3. As such, CDK4/6 can be a therapeutic target in Flt3 ITD AML but also in primary Flt3 wt AML. Finally, acquired resistance to CDK4/6 inhibition can arise through activation CDK2.
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Nuga, Oluwademilade, Yuling Meng, Artem Berezovsky, Kevin Nelson, and Ana de Carvalho. "EXTH-36. PHARMACEUTICAL INHIBITION OF CYCLIN DEPENDENT KINASE 4/6 (CDK4/6) IN GLIOBLASTOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii94—ii95. http://dx.doi.org/10.1093/neuonc/noaa215.390.
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Abstract Potent and selective CDK4/6 inhibitors (CDK4/6i) have potential for treating glioblastoma. Although genomic abnormalities affecting CDK4/6-RB1 signaling axis, such as CDK4 or CDK6 amplification and CDKN2A deletion, which are frequent in GBM, have been proposed to predict response of RB1-wildtype GBM to CDK4/6i, there is not enough data validating these biomarkers as sufficient for patient selection. Here we employ a panel of GBM patient derived cancer stem cells (CSC) representing the most frequent somatic genomic alterations in GBM to test their response to CDK4/6i. Twelve CSC lines were treated in quintuplicate for 4–7 days with 0–10 mM Abemaciclib, Ribociclib or vehicle control. Cell viability was measured using CellTiterGlo and dose response curves were analyzed using GRmetrics in R to determine Area Above the Curve (AAC) and IC50, factoring variable growth rates among cell lines. Experiments were repeated 2–4 times. Abemaciclib was more potent in reducing cell viability, based on the RB1-null CSC line measured resistance (mean AAC = 0.3 +/- 0.06), ribociclib was more specific (mean AAC = 0.05 +/-0.01). 4/7 CSCs with CDKN2A homozygous deletion were sensitive (mean AAC > 0.7) while 3/7 were resistant (mean AAC < 0.33) to 4 and 7-day treatments of abemaciclib. One CSC from a newly diagnosed GBM bearing CDK4, MYC and EGFR amplifications was sensitive to both inhibitors (mean AAC = 0.5 abemaciclib and ribociclib), while CSC from the matched recurrent tumor presenting the same driver genomic alterations was significantly more resistant (mean AAC = 0.2 for abemaciclib and ribociclib) (p < 0.05, t-test). Additionally, we exposed a sensitive cell line to conditioned media from a resistant cohort, resulting in significantly reduced proliferation and increased resistance to CDK4/6i (p< 0.05, Dunn). These findings underscore the importance of a utilizing a robust molecular profiling approach in evaluating which patients will benefit from CDK4/6i therapy.
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Huang, Xiangao, Maurizio Di Liberto, Tracey Louie, David S. Jayabalan, Scott Ely, Ruben Niesvizky, and Selina Chen-Kiang. "Selective Inhibition of CDK4 and CDK6 Primes Chemoresistant Myeloma Cell for Cytotoxic Killing through Induction of Cell Cycle-Coupled Mitochondrial Dysfunction and Apoptosis." Blood 112, no. 11 (November 16, 2008): 3678. http://dx.doi.org/10.1182/blood.v112.11.3678.3678.
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Abstract Dysregulation of cyclin-dependent kinase (CDK)4 or CDK6 activity by gain of function or loss of inhibition is one of the most frequent aberrations in cancer. This includes multiple myeloma (MM), where overexpression of CDK4 (CDK6) precedes unrestrained proliferation of CD138+ bone marrow myeloma cells in vivo, in particular during aggressive tumor growth and relapse. In complex with the D-type cyclin, CDK4 and CDK6 promote cell cycle entry and progression through G1 by inactivating the retinoblastoma protein Rb and antagonizing the INK4 family of CDK inhibitors, suggesting that inhibition of CDK4/6 is a promising approach for cell cycle control in MM. We have now developed a novel approach to both halt cell proliferation and enhance cytotoxic killing of MM cells by selective inhibition of CDK4/6 in combination with cytotoxic agents. We show that knocking down CDK4 and CDK6 expression by shRNA interference or inhibiting CDK4/6 activity with PD 0332991, the only known CDK4/6-specific small molecule inhibitor, leads to sustained G1 arrest and induction of synchronous cell cycle progression upon removal of PD 0332991. Induction of sustained early G1 arrest is not accompanied by apoptosis. However, it primes MM cells for synergistic killing by low dose cytotoxic agents of diverse modes of action, which is further augmented during synchronous S phase entry. Most importantly, induction of sustained G1 arrest with PD 0332991 primes freshly isolated chemoresistant CD138+ bone marrow myeloma cells for killing by low dose proteasome inhibitors in the presence of bone marrow stromal cells. Synergistic killing by PD 0332991 combined with low dose bortezomib (2–6 nM) in early G1 (referred to as PD-B) is mediated by increased neutralization of Mcl-1 and Bcl-2 in the absence of Noxa, as PD-B augments bortezomib activation of Bim and Mcl-1 transcription while silencing Noxa in early G1. This leads to aggregation of Bak, but not Bax, on the mitochondria, mitochondrial membrane depolarization, preferential release of Smac/DIABLO, but not cytochrome c, from mitochondria, reduction of c-IAP and caspase-9 activation. Apoptosis is further amplified through activation of caspase-8 without inducing TRAIL, FASL and TNF-α, the major ligands that trigger the extrinsic apoptosis pathway. Cytotoxic killing by PD-B is recapitulated in synergistic tumor suppression in animal models. Collectively, our ex vivo and in vivo data demonstrate that PD-B induces synergistic killing of MM cells through cell cycle-coupled regulation of Bcl-2 family genes and induction of mitochondrial dysfunction. As PD 0332991 is orally bio-available, potent and low in toxicity, our approaches have formed the basis for an ongoing, first-inclass Phase I/II clinical trial to selectively target CDK4/6 with PD 0332991 in combination with bortezomib and dexamethasone in multiple myeloma. Selective targeting CDK4 and CDK6 in combination with cytotoxic killing, therefore, provides a new and promising mechanism-based therapeutic strategy for multiple myeloma and potentially other cancers.
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Pernas, Sonia, Sara M. Tolaney, Eric P. Winer, and Shom Goel. "CDK4/6 inhibition in breast cancer: current practice and future directions." Therapeutic Advances in Medical Oncology 10 (January 1, 2018): 175883591878645. http://dx.doi.org/10.1177/1758835918786451.
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The cyclin D/cyclin-dependent kinases 4 and 6 (CDK4/6)–retinoblastoma protein (RB) pathway plays a key role in the proliferation of both normal breast epithelium and breast cancer cells. A strong rationale for inhibiting CDK4/6 in breast cancers has been present for many years. However, potent and selective CDK4/6 inhibitors have only recently become available. These agents prevent phosphorylation of the RB tumor suppressor, thereby invoking cancer cell cycle arrest in G1. CDK4/6 inhibitors have transited rapidly from preclinical studies to the clinical arena, and three have already been approved for the treatment of advanced, estrogen receptor (ER)-positive breast cancer patients on account of striking clinical trial results demonstrating substantial improvements in progression-free survival. ER-positive breast cancers harbor several molecular features that would predict their sensitivity to CDK4/6 inhibitors. As physicians gain experience with using these agents in the clinic, new questions arise: are CDK4/6 inhibitors likely to be useful for patients with other subtypes of breast cancer? Are there other agents that could be effectively combined with CDK4/6 inhibitors, beyond endocrine therapy? Is there a rationale for combining CDK4/6 inhibitors with novel immune-based therapies? In this review, we describe not only the clinical data available to date, but also the biology of the CDK4/6 pathway and discuss answers to these questions. In particular, we highlight that CDK4 and CDK6 govern much more than the cancer cell cycle, and that their optimal use in the clinic depends on a deeper understanding of the less well characterized effects of these enzymes.
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Sobhani, Navid, Anne Fassl, Giuseppina Mondani, Daniele Generali, and Tobias Otto. "Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer." Cells 10, no. 2 (February 1, 2021): 293. http://dx.doi.org/10.3390/cells10020293.
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Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)—in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.
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Kamboj, Jasmine, Elie Chalhoub, and Peter E. Friedell. "Reversible Macrocytosis with Cyclin Dependent Kinase Inhibitors." Blood 132, Supplement 1 (November 29, 2018): 4882. http://dx.doi.org/10.1182/blood-2018-99-113380.
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Abstract Introduction Cyclin-dependant kinases (CDKs) are a family of serine threonine kinases regulating cell cycle progression. The interaction of cyclin D (encoded by CCND1) with CDK4/6 helps in hyper-phosphorylation of the retinoblastoma (Rb) gene product, which further facilitates in progression through G1 to S phase of the cell cycle. Oncogenic signals in Hormone Receptor(HR)-positive breast cancer facilitate CCND1 amplification and overexpression of CDK4/6 to drive breast cancer proliferation and are associated with endocrine resistance in breast cancer. CDK4/6 inhibitors selectively inhibit CDK4 and CDK6, resulting in loss of RB1 phosphorylation, henceforth blocking cell cycle progression and causing G1 phase arrest. These agents have profound activity in hormone receptor positive breast cancer cell lines and work synergistically with endocrine therapies to combat endocrine resistance in breast cancer. Neutropenia is a known side effect of CDK4/6 inhibitors, with an incidence as high as 70%. Anemia as a side effect has been reported with low incidence. We report macrocytosis in patients receiving CDK4/6 inhibitors. Methods Retrospective analysis was performed at Sanford Health Bemidji. IRB approval was sought prior to initiation of the review. All patients who received CDK4/6 inhibitor in combination with hormonal therapy from 1/2016-2/2018 were included. Dates for initiating CDK4/6 inhibitor, onset of macrocytosis, maximum mean corpuscular volume (MCV-max) achieved, correlation of time with rising MCV (MCV-t) and normalization of MCV in the absence of CDK4/6 inhibitor (reversibility of macrocytosis) was documented. Complete Blood Count (CBC) was reviewed. Work up for elevated MCV was performed in each patient. Bone marrow biopsies were not performed. Results Table. All patients (n=6) had rising MCV, within 4-6 weeks of initiation of the CDK4/6 inhibitor. Time to achieve MCV more than 100, varied from 3 to 7 months, this timing did not correlate well with baseline MCV. Progressively rising MCV with the duration of use of CDK4/6 inhibitor was seen. Reversibility of MCV was seen in 3 patients (Case B, C and D) who had interruption of CDK4/6 inhibitor for health related issues. Normalization of MCV on discontinuation of CDK4/6 inhibitor and rise in MCV on resumption of CDK4/6 inhibitor was seen. Hemoglobin drop from the baseline was not seen in any of the patients. Apart from neutropenia and macrocytosis, no other abnormality was seen on CBC. Stability of disease was documented in all patients on first set of scans done at 3 months and radiologic complete remission was documented in approximately 6-9 months of being on CDK4/6 inhibition. Macrocytosis workup was performed in all patients, including vitamin B12, folic acid, TSH, reticulocyte count, peripheral smear reviews and liver function tests. Vitamin B12 was low normal in case D, and was supplemented, without any changes seen on MCV. Conclusions CDK4/6 inhibition has become extremely prevalent in the recent times for hormone receptor positive breast cancer. We hypothesize that CDK4/6 inhibition produces reversible macrocytic anemia of unknown clinical significance. Given all patients had elevation in MCV along with complete radiologic remission, there is a possible causal relationship of elevated MCV and treatment response. The long-term clinical significance of observed macrocytosis and possible dysplasia, are important questions that need to be answered in large clinical trials. Disclosures No relevant conflicts of interest to declare.
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Goel, Shom, Molly J. DeCristo, April C. Watt, Haley BrinJones, Jaclyn Sceneay, Ben B. Li, Naveed Khan, et al. "CDK4/6 inhibition triggers anti-tumour immunity." Nature 548, no. 7668 (August 2017): 471–75. http://dx.doi.org/10.1038/nature23465.
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Arnheim, Katharina. "Erste OS-Daten zur CDK4/6-Inhibition." InFo Onkologie 21, no. 8 (December 2018): 70. http://dx.doi.org/10.1007/s15004-018-6352-5.
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Gampenrieder, Simon Peter, Gabriel Rinnerthaler, and Richard Greil. "CDK4/6 inhibition in luminal breast cancer." memo - Magazine of European Medical Oncology 9, no. 2 (June 2016): 76–81. http://dx.doi.org/10.1007/s12254-016-0268-2.
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Heim, Thomas. "Inhibition von CDK4/6 beim fortgeschrittenen Brustkrebs." Im Focus Onkologie 21, no. 10 (October 2018): 66. http://dx.doi.org/10.1007/s15015-018-4245-y.
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AbuHammad, Shatha, Carleen Cullinane, Claire Martin, Zoe Bacolas, Teresa Ward, Huiqin Chen, Alison Slater, et al. "Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma." Proceedings of the National Academy of Sciences 116, no. 36 (August 22, 2019): 17990–8000. http://dx.doi.org/10.1073/pnas.1901323116.
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Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5–MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5–MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.
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Yuan, Kai, Wenjian Min, Xiao Wang, Jiaxing Li, Wenbin Kuang, Fang Zhang, Shengnan Xie, and Peng Yang. "Discovery of novel and selective CDK4/6 inhibitors by pharmacophore and structure-based virtual screening." Future Medicinal Chemistry 12, no. 12 (June 2020): 1121–36. http://dx.doi.org/10.4155/fmc-2020-0011.
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Aim: CDK4 and 6 are the key initiators in the transition from G1 to S phase in the cell cycle; thus, inhibition of CDK4/6 is a promising strategy for cancer treatment. Materials & methods: The Specs database and an in-house library were screened via the pharmacophore model and LibDock protocol and then the retrieved hits were clustered into 100 clusters. The CDK4/6 inhibitory activity of selected compounds was evaluated by CDK enzymatic assays, followed by chemical optimization of the top hit compound. Results & conclusion: The integration of pharmacophores and molecular docking offered us an effective method to discover the novel CDK4/6 inhibitor 10 and further chemical optimization led to the highly selective and potent CDK4/6 inhibitor 18, which exhibited potential for the treatment of multiple myeloma.
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Santiappillai, Nancy T., Shatha Abuhammad, Alison Slater, Laura Kirby, Grant A. McArthur, Karen E. Sheppard, and Lorey K. Smith. "CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway." Cancers 13, no. 3 (January 29, 2021): 524. http://dx.doi.org/10.3390/cancers13030524.
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Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical development. CDK4/6 regulate the cell cycle via phosphorylation and inhibition of the tumour suppressor RB, and in addition can phosphorylate many cellular proteins and modulate numerous cellular functions including cell metabolism. Metabolic reprogramming is observed in melanoma following standard-of-care BRAF/MEK inhibition and is involved in both therapeutic response and resistance. In preclinical models, CDK4/6 inhibitors overcome BRAF/MEK inhibitor resistance, leading to sustained tumour regression; however, the metabolic response to this combination has not been explored. Here, we investigate how CDK4/6 inhibition reprograms metabolism and if this alters metabolic reprogramming observed upon BRAF/MEK inhibition. Although CDK4/6 inhibition has no substantial effect on the metabolic phenotype following BRAF/MEK targeted therapy in melanoma, CDK4/6 inhibition alone significantly enhances mitochondrial metabolism. The increase in mitochondrial metabolism in melanoma cells following CDK4/6 inhibition is fuelled in part by both glutamine metabolism and fatty acid oxidation pathways and is partially dependent on p53. Collectively, our findings identify new p53-dependent metabolic vulnerabilities that may be targeted to improve response to CDK4/6 inhibitors.
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Pandey, Kamal, Nahee Park, Kyung-Soon Park, Jin Hur, Yong Bin Cho, Minsil Kang, Hee-Jung An, Sewha Kim, Sohyun Hwang, and Yong Wha Moon. "Combined CDK2 and CDK4/6 Inhibition Overcomes Palbociclib Resistance in Breast Cancer by Enhancing Senescence." Cancers 12, no. 12 (November 29, 2020): 3566. http://dx.doi.org/10.3390/cancers12123566.
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Breast cancer represents the number one global cancer burden in women and the hormone receptor (HR)-positive subtype comprises approximately 70% of breast cancers. Unfortunately, acquired resistance ultimately occurs in almost all cases, even though cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for HR-positive/human epidermal growth factor receptor 2-negative subtype. Here, we investigated mechanisms of resistance to CDK4/6 inhibitor and potential therapeutic strategies using our palbociclib-resistant preclinical model. We observed that cyclin E was significantly overexpressed in palbociclib-resistant cells, and similar association was also confirmed in pleural effusion samples collected from HR-positive breast cancer patients. After confirmation of cyclin E-CDK2 interaction by co-immunoprecipitation, we demonstrated CDK2 inhibition combined with palbociclib synergistically suppressed proliferation of palbociclib-resistant cells and growth of palbociclib-resistant xenograft in mice. We also proved that enhancing C-MYC-mediated senescence is a novel mechanism behind the synergism created by targeting both CDK2 and CDK4/6. Furthermore, the clinical relevance of cyclin E as a therapeutic target was supported by significant association between CCNE1 overexpression and poor prognosis based on large-scale public gene expression data sets in HR-positive breast cancer patients. Therefore, we propose cyclin E-CDK2 signaling as a promising therapeutic target for overcoming cyclin E-associated resistance to CDK4/6 inhibitor.
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Huang, Xiangao, Kathryn Bailey, Maurizio Di Liberto, Francesco Parlati, Ruben Niesvizky, Susan Demo, and Selina Chen-Kiang. "Induction of Sustained Early G1 Arrest by Selective Inhibition of CDK4 and CDK6 Primes Myeloma Cells for Synergistic Killing by Proteasome Inhibitors Carfilzomib and PR-047." Blood 112, no. 11 (November 16, 2008): 3670. http://dx.doi.org/10.1182/blood.v112.11.3670.3670.
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Abstract Targeting the cell cycle in combination with cytotoxic killing is a rational approach to cancer therapy. Dysregulation of the cyclin-dependent kinases CDK4 and CDK6 precedes uncontrolled proliferation of myeloma cells in vivo, in particular during relapse and drug resistance. This finding reinforces the critical importance of targeting CDK4/6 in myeloma, but success with broad-spectrum CDK inhibitors has been modest. Using the only known selective inhibitor of CDK4/6, PD 0332991, we have developed a novel approach to prime chemoresistant myeloma cells for synergistic killing by diverse cytotoxic agents. We show that selective inhibition of CDK4/6 by PD 0332991 leads to sustained cell cycle arrest in early G1 in the absence of apoptosis. However, it markedly augments cytotoxic killing by PR-171 (carfilzomib), a selective inhibitor of the chymotrypsin-like activity of the proteasome, or PR-047, an orally bioavailable analog of carfilzomib. Synergistic killing of myeloma cells arrested in early G1 by carfilzomib (or PR-047) is caspase-dependent, and requires only a brief (one hour) exposure to the proteasome inhibitor at concentrations as low as 60 nM. This effect is mediated by synergistic and rapid induction of mitochondrial membrane depolarization and activation of downstream caspase-9 within 6 hours of removal of carfilzomib or PR-047. As PD 0332991 acts as an ATP-competitive inhibitor of the CDK4/6 kinase domain, inhibition of CDK4/6 and the cell cycle by PD 0332991 is reversible. Importantly, targeting CDK4/6 with PD 0332991 in combination with either carfilzomib or PR-047 leads to complete eradication of myeloma cells ex vivo, in contrast to the combination of PD 0332991 with other proteasome inhibitors. Selective inhibition of CDK4/6 in combination with carfilzomib (or PR-047), therefore, not only halts cell proliferation but also potently induces synergistic killing that is likely to eliminate cell cycle reentry and generation of resistant cells. PD 0332991 is a small molecule with bio-availability and proven tumor suppressing activity in both human myeloma xenograft and immunocompetent mouse myeloma models. It is well tolerated in humans as shown by the ongoing Phase I/II clinical trials in myeloma and previous phase I trials in mantle cell lymphoma and solid tumors. Evidence from Phase I trials of carfilzomib indicates that it is also well tolerated, in fact, the peripheral neuropathy that is commonly observed with proteasome inhibitor bortezomib appears to be less severe and possibly less frequent. Mechanism-based targeting of CDK4/6 in combination with selective proteasome inhibitors, like carfizomib and PR-047, thus represents a new and promising therapeutic strategy for multiple myeloma and potentially other hematopoietic malignancies.
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Shaltiel, Indra A., Alba Llopis, Melinda Aprelia, Rob Klompmaker, Apostolos Menegakis, Lenno Krenning, and René H. Medema. "Combined Inactivation of Pocket Proteins and APC/CCdh1 by Cdk4/6 Controls Recovery from DNA Damage in G1 Phase." Cells 10, no. 3 (March 4, 2021): 550. http://dx.doi.org/10.3390/cells10030550.
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Most Cyclin-dependent kinases (Cdks) are redundant for normal cell division. Here we tested whether these redundancies are maintained during cell cycle recovery after a DNA damage-induced arrest in G1. Using non-transformed RPE-1 cells, we find that while Cdk4 and Cdk6 act redundantly during normal S-phase entry, they both become essential for S-phase entry after DNA damage in G1. We show that this is due to a greater overall dependency for Cdk4/6 activity, rather than to independent functions of either kinase. In addition, we show that inactivation of pocket proteins is sufficient to overcome the inhibitory effects of complete Cdk4/6 inhibition in otherwise unperturbed cells, but that this cannot revert the effects of Cdk4/6 inhibition in DNA damaged cultures. Indeed, we could confirm that, in addition to inactivation of pocket proteins, Cdh1-dependent anaphase-promoting complex/cyclosome (APC/CCdh1) activity needs to be inhibited to promote S-phase entry in damaged cultures. Collectively, our data indicate that DNA damage in G1 creates a unique situation where high levels of Cdk4/6 activity are required to inactivate pocket proteins and APC/CCdh1 to promote the transition from G1 to S phase.
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Olanich, Mary E., Wenyue Sun, Stephen M. Hewitt, Zied Abdullaev, Svetlana D. Pack, and Frederic G. Barr. "CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma." Clinical Cancer Research 21, no. 21 (March 25, 2015): 4947–59. http://dx.doi.org/10.1158/1078-0432.ccr-14-2955.
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Piezzo, Michela, Stefania Cocco, Roberta Caputo, Daniela Cianniello, Germira Di Gioia, Vincenzo Di Lauro, Giuseppina Fusco, et al. "Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors." International Journal of Molecular Sciences 21, no. 18 (September 4, 2020): 6479. http://dx.doi.org/10.3390/ijms21186479.
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Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.
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Ding, Qing-Ming, Tien C. Ko, and B. Mark Evers. "Caco-2 intestinal cell differentiation is associated with G1 arrest and suppression of CDK2 and CDK4." American Journal of Physiology-Cell Physiology 275, no. 5 (November 1, 1998): C1193—C1200. http://dx.doi.org/10.1152/ajpcell.1998.275.5.c1193.
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The cellular mechanisms regulating intestinal proliferation and differentiation remain largely undefined. Previously, we showed an early induction of the cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1 in Caco-2 cells, a human colon cancer line that spontaneously differentiates into a small bowel phenotype. The purpose of our present study was to assess the timing of cell cycle arrest in relation to differentiation in Caco-2 cells and to examine the mechanisms responsible for CDK inactivation. Caco-2 cells undergo a relative G1/S block and cease to proliferate at day 3 postconfluency; an increase in the activity of terminally differentiated brush-border enzymes (sucrase and alkaline phosphatase) was noted at day 6 postconfluency. Cell cycle block was associated with suppression of both CDK2 and CDK4 activities, which are important for G1/S progression. Treatment of the CDK immune complexes with the detergent deoxycholate (DOC) resulted in restoration of CDK2, but not CDK4, activity at day 3postconfluency, suggesting the presence of inhibitory protein(s) binding to the cyclin/CDK2 complex at this time point. An increased binding of p21Waf1/Cip1 to CDK2 complexes at day 3 postconfluency was noted, suggesting a potential role for p21Waf1/Cip1in CDK2 inactivation; however, immunodepletion of p21Waf1/Cip1 from Caco-2 protein extracts demonstrated that p21Waf1/Cip1 is only partially responsible for CDK2 suppression at day 3postconfluency. A decrease in the cyclin E/CDK2 complex appears to contribute to the CDK2 inactivation noted at days 6 and 12 postconfluency. Taken together, our results suggest that multiple mechanisms contribute to CDK suppression during Caco-2 cell differentiation. Inhibition of CDK2 and CDK4 leads to G1 arrest and inhibition of proliferation that precede Caco-2 cell differentiation.
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Böhm, Michael J., Ralf Marienfeld, Daniela Jäger, Kevin Mellert, Adrian von Witzleben, Silke Brüderlein, Mathias Wittau, et al. "Analysis of the CDK4/6 Cell Cycle Pathway in Leiomyosarcomas as a Potential Target for Inhibition by Palbociclib." Sarcoma 2019 (January 21, 2019): 1–10. http://dx.doi.org/10.1155/2019/3914232.
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Leiomyosarcoma (LMS) is characterized by high genomic complexity, and to date, no specific targeted therapy is available. In a genome-wide approach, we profiled genomic aberrations in a small cohort of eight primary tumours, two relapses, and eight metastases across nine different patients. We identified CDK4 amplification as a recurrent alteration in 5 out of 18 samples (27.8%). It has been previously shown that the LMS cell line SK-LMS-1 has a defect in the p16 pathway and that this cell line can be inhibited by the CDK4 and CDK6 inhibitor palbociclib. For SK-LMS-1 we confirm and for SK-UT-1 we show that both LMS cell lines express CDK4 and that, in addition, strong CDK6 expression is seen in SK-LMS-1, whereas Rb was expressed in SK-LMS-1 but not in SK-UT-1. We confirm that inhibition of SK-LMS-1 with palbociclib led to a strong decrease in protein levels of Phospho-Rb (Ser780), a decreased cell proliferation, and G0/G1-phase arrest with decreased S/G2fractions. SK-UT-1 did not respond to palbociclib inhibition. To compare thesein vitrofindings with patient tissue samples, a p16, CDK4, CDK6, and p-Rb immunohistochemical staining assay of a large LMS cohort (n=99patients with 159 samples) was performed assigning a potential responder phenotype to each patient, which we identified in 29 out of 99 (29.3%) patients. Taken together, these data show that CDK4/6 inhibitors may offer a new option for targeted therapy in a subset of LMS patients.
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Goel, Shom, and Jean J. Zhao. "CDK4/6 inhibition: the late harvest cycle begins." Oncotarget 7, no. 31 (May 24, 2016): 48854–56. http://dx.doi.org/10.18632/oncotarget.9576.
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Battisti, Nicolò Matteo Luca, and Alistair Ring. "CDK4/6 inhibition in HER2-positive breast cancer." Lancet Oncology 21, no. 6 (June 2020): 734–35. http://dx.doi.org/10.1016/s1470-2045(20)30164-9.
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Facharztmagazine, Redaktion. "Neue Leitlininenempfehlungen zur CDK4/6-Inhibition bei Brustkrebs." Im Fokus Onkologie 23, no. 6 (December 2020): 72. http://dx.doi.org/10.1007/s15015-020-2697-3.
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Di Li berto, Maurizio, Xiangao Huang, Amy Chadburn, Peter Martin, Ruben Niesvizky, Scott Ely, John P. Leonard, and Selina Chen Kiang. "Selective Inhibition of CDK4 and CDK6 Primes Chemoresistant MCL Cells for Killing by Proteasome Inhibitor Bortezomib by Activating Cell Cycle-Coupled Apoptosis." Blood 112, no. 11 (November 16, 2008): 3624. http://dx.doi.org/10.1182/blood.v112.11.3624.3624.
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Abstract Mantle Cell Lymphoma (MCL) remains generally incurable, suggesting that more effective control of unrestrained tumor growth is essential. Loss of cell cycle control is a hallmark of cancer, in particular of MCL where cell cycle progression through G1 is accelerated due to elevation of cyclin-dependent kinase 4 (CDK4) and constitutive cyclin D1 expression. Thus, one rational approach to improve MCL therapy is to target CDK4/6 in combination with cytotoxic killing. Although success in targeting the cell cycle in cancer with broad-spectrum CDK inhibitors has been modest, PD 0332991, the only known CDK4/6-specific inhibitor with oral bioavailability, has been shown to selectively and potently inhibit CDK4/6 in MCL cells ex vivo. Additionally, in a proof-of-mechanism study in patients with recurrent MCL, we have found that PD 0332991 is well tolerated, and effective in inhibiting CDK4 and CDK6 and suppressing tumor growth in vivo. Of note, 50% of the patients (8/16) have achieved a stable disease for greater then 40 weeks (Leonard et al, abstract submitted to ASH 2008). These findings suggest that selective targeting of CDK4 and CDK6 with PD 0332991 is a promising therapy for MCL. To advance targeting of the cell cycle in cancer, we have developed two novel approaches to both inhibit tumor cell proliferation and activate cell cycle-coupled apoptosis in MCL. We show in primary MCL tumor cells and MCL cell lines by BrdU pulse labeling and DNA content analysis that selective inhibition of CDK4/6 with PD 0332991 leads to a complete G1 arrest, despite high level of c-Myc expression and extensive chromosomal abnormality. As PD 0332991 acts reversibly, removal of PD 0332991 immediately releases the G1 block and induces synchronous (>90%) G1-S cell cycle progression and S phase entry. This sensitizes chemoresistant MCL cells to killing by suboptimal doses of cytotoxic agents such as bortezomib, through activating cell cycle-coupled apoptosis during S phase entry. Synergistic killing of MCL cells by induction of cell cycle synchronization with PD 0332991 in combination with bortezomib is mediated by induction of mitochondrial membrane depolarization and activation of caspase-9. In a complementary study, we have demonstrated that selective targeting of CDK4 and CDK6 by PD 0332991 similarly primes chemoresistant primary myeloma cells for cytotoxic killing by activating cell cycle-coupled apoptosis, and induces synergistic tumor suppression in animal models. Selective targeting of CDK4 and CDK6 by PD 0332991 in combination with cytotoxic killing, therefore, represents a promising new strategy for cell cycle-based therapy for MCL and other hematopoietic malignancies.
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Li, Ji, Porter, Broude, Roninson, and Chen. "Characterizing CDK8/19 Inhibitors through a NFκB-Dependent Cell-Based Assay." Cells 8, no. 10 (October 6, 2019): 1208. http://dx.doi.org/10.3390/cells8101208.
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Cell-based assays for CDK8/19 inhibition are not easily defined, since there are no known cellular functions unique to these kinases. To solve this problem, we generated derivatives of 293 cells with CRISPR knockout of one or both of CDK8 and CDK19. Double knockout (dKO) of CDK8 and CDK19 together (but not individually) decreased the induction of transcription by NFκB (a CDK8/19-potentiated transcription factor) and abrogated the effect of CDK8/19 inhibitors on such induction. We generated wild type (WT) and dKO cell lines expressing luciferase from an NFκB-dependent promoter. Inhibitors selective for CDK8/19 over other CDKs decreased TNFα-induced luciferase expression in WT cells by ~80% with no effect on luciferase induction in dKO cells. In contrast, non-selective CDK inhibitors flavopiridol and dinaciclib and a CDK7/12/13 inhibitor THZ1 (but not CDK4/6 inhibitor palbociclib) suppressed luciferase induction in both WT and dKO cells, indicating a distinct role for other CDKs in the NFκB pathway. We used this assay to characterize a series of thienopyridines with in vitro bone anabolic activity, one of which was identified as a selective CDK8/19 inhibitor. Thienopyridines inhibited luciferase induction in the WT but not dKO cells and their IC50 values in the WT reporter assay showed near-perfect correlation (R2 = 0.98) with their reported activities in a bone anabolic activity assay, confirming that the latter function is mediated by CDK8/19 and validating our assay as a robust and quantitative method for CDK8/19 inhibition.
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Yin, Lei, Zhenglin Yao, Yue Wang, Julius Huang, Michelle Mazuranic, and Ang Yin. "Preclinical evaluation of novel CDK4/6 inhibitor GLR2007 in glioblastoma models." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e14023-e14023. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e14023.
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e14023 Background: Glioblastoma multiforme (GBM) is characterized by a high frequency of cyclin-dependent kinase (CDK)4 and CDK6 pathway dysregulation. CDK4/6 inhibitors palbociclib and abemaciclib are approved for the treatment of breast cancer, but poor blood–brain barrier (BBB) penetration limits their efficacy in GBM. GLR2007 is a novel CDK4/6 inhibitor with potential for improved penetration across the BBB. Here, we report on the activity of GLR2007 in GBM cell lines and its anti-tumor efficacy in mouse xenograft models. Methods: Three in vitro assays were used to assess the activity of GLR2007. Inhibition of CDK4/6 enzymatic activity by GLR2007 or palbociclib was calculated, and cell cycle stages were analyzed in U87-MG cells treated with vehicle control or GLR2007 for 24 h. Cell viability was evaluated in U87-MG and U118-MG cell lines after culture for 72 h with GLR2007 or abemaciclib. In vivo evaluation of the anti-tumor efficacy of GLR2007 versus vehicle, abemaciclib, and/or palbociclib was performed in BALB/c nude mouse GBM xenograft models. Quantitative whole-body autoradiography was used to determine the distribution of [14C]GLR2007 in the tissues of Sprague Dawley rats. Results: GLR2007 potency toward CDK4 and CDK6 was 33.1 and 3.8 times that of palbociclib, respectively. At concentrations >13.72 nM, GLR2007 caused G1 arrest of U87-MG cells. GLR2007 inhibited proliferation in U87-MG cells (IC50 15.6±2.4 nM) and U118-MG cells (IC50 23.2±5.2 nM). Anti-tumor efficacy of GLR2007 versus vehicle control was observed in two mouse GBM xenograft models (Table). Studies performed in rats demonstrated the distribution of [14C]GLR2007 in whole brain tissue following a single oral dose, with total radioactivity levels in the brain exceeding those in plasma by 2.3–4.5-fold from 2–6 h after dosing. Conclusions: These preclinical studies demonstrate the potential of GLR2007 as a novel CDK4/6 inhibitor for treatment of GBM. GLR2007 showed numerically greater anti-tumor efficacy than approved CDK4/6 inhibitors in xenograft models, and evidence of substantial central nervous system penetration. [Table: see text]
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Ohara, Masahiro, Kengo Saito, Ken Kageyama, Mizue Terai, Hanyin Cheng, Andrew E. Aplin, and Takami Sato. "Dual Targeting of CDK4/6 and cMET in Metastatic Uveal Melanoma." Cancers 13, no. 5 (March 4, 2021): 1104. http://dx.doi.org/10.3390/cancers13051104.
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Uveal melanoma (UM) is the most common cancer of the eye in adults. Up to 50% of UM patients subsequently develop metastases, especially in the liver. It has been reported that the retinoblastoma (RB) pathway is deregulated in more than 90% of UM despite the rarity of mutations in the RB1 gene itself. CDK4/6 inhibition (CDK4/6i) is a rational strategy for treatment of UM. In this report, we investigated the antiproliferative activity of a selective CDK4/6 inhibitor on metastatic UM. A CDK4/6 inhibitor suppressed UM cell lines growth in in vitro and in vivo experiments. Hepatocyte growth factor (HGF) decreased the effect of CDK4/6 inhibitor on metastatic UM cell lines. When CDK4/6i was combined with cMET inhibitor, enhanced growth suppression was observed in metastatic UM tumors grown in human-HGF knock-in xenograft mouse models. HGF is enriched in the liver and the majority of liver metastases from UM express activated forms of cMET; therefore, signaling through cMET could contribute to the resistance mechanisms against CDK4/6i, especially in UM patients with hepatic metastasis. Together, these results provide a rationale for the use of cMET inhibitor in combination with a CDK4/6 inhibitor for the treatment of metastatic UM.
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Murphy, Conleth G., and Maura N. Dickler. "The Role of CDK4/6 Inhibition in Breast Cancer." Oncologist 20, no. 5 (April 15, 2015): 483–90. http://dx.doi.org/10.1634/theoncologist.2014-0443.
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Goel, Shom, Molly J. DeCristo, Sandra S. McAllister, and Jean J. Zhao. "CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest." Trends in Cell Biology 28, no. 11 (November 2018): 911–25. http://dx.doi.org/10.1016/j.tcb.2018.07.002.
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Scott, Susan Combs, Sarah S. Lee, and Jame Abraham. "Mechanisms of therapeutic CDK4/6 inhibition in breast cancer." Seminars in Oncology 44, no. 6 (December 2017): 385–94. http://dx.doi.org/10.1053/j.seminoncol.2018.01.006.
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Einecke, Dirk. "Praxisdaten bestätigen: länger ohne Progress unter CDK4/6-Inhibition." InFo Hämatologie + Onkologie 23, no. 5 (May 2020): 55. http://dx.doi.org/10.1007/s15004-020-8083-7.
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Álvarez-Fernández, Mónica, and Marcos Malumbres. "Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition." Cancer Cell 37, no. 4 (April 2020): 514–29. http://dx.doi.org/10.1016/j.ccell.2020.03.010.
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