Journal articles on the topic 'RAS wild type'
To see the other types of publications on this topic, follow the link: RAS wild type.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'RAS wild type.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Anastassiadis, Theonie, and Eric J. Brown. "Wild-Type RAS: Keeping Mutant RAS in CHK." Cancer Cell 25, no. 2 (February 2014): 137–38. http://dx.doi.org/10.1016/j.ccr.2014.01.029.
Full text
2
Fotiadou, Poppy P., Chiaki Takahashi, Hasan N. Rajabi, and Mark E. Ewen. "Wild-Type NRas and KRas Perform Distinct Functions during Transformation." Molecular and Cellular Biology 27, no. 19 (July 16, 2007): 6742–55. http://dx.doi.org/10.1128/mcb.00234-07.
Full textAbstract:
ABSTRACT The ras proto-oncogenes, of which there are four isoforms, are molecular switches that function in signal transduction pathways to control cell differentiation, proliferation, and survival. How the Ras isoforms orchestrate cellular processes that affect behavior is poorly understood. Further, why cells express two or more Ras isoforms is unknown. Here, using a genetically defined system, we show that the presence of both wild-type KRas and NRas isoforms is required for transformation because they perform distinct nonoverlapping functions: wild-type NRas regulates adhesion, and KRas coordinates motility. Remarkably, we find that Ras isoforms achieve functional specificity by engaging different signaling pathways to affect the same cellular processes, thereby coordinating cellular outcome. Although we find that signaling from both isoforms intersects in actin and microtubule cytoskeletons, our results suggest that KRas signals through Akt and Cdc42 while NRas signals through Raf and RhoA. Our analyses suggest a previously unappreciated convergence of different Ras isoforms on the dynamics of the processes involved in transformation.
3
Singh, Arvind, A. Pavani Sowjanya, and Gayatri Ramakrishna. "The wild‐type Ras: road ahead." FASEB Journal 19, no. 2 (February 2005): 161–69. http://dx.doi.org/10.1096/fj.04-2584hyp.
Full text
4
Henry, Jason, Jason Willis, Christine Megerdichian Parseghian, Kanwal Pratap Singh Raghav, Benny Johnson, Arvind Dasari, David Stone, et al. "NeoRAS: Incidence of RAS reversion from RAS mutated to RAS wild type." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 180. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.180.
Full textAbstract:
180 Background: RAS mutations are found in ~50% of patients (pts) with metastatic colorectal cancer (mCRC) and associated with resistance to anti-EGFR. Circulating tumor DNA (ctDNA) enables detection of resistant RASMUT arising from RASWT. Recently there has been interest in defining the converse: RASMUT tumors that revert to RASWT, with early results suggesting rates of ~7%. Clinical trials in this population are in development, though the incidence has not been validated with robust methodologies. Methods: 1) We identified 74 mCRC pts with baseline RASMUT and longitudinal ctDNA or tissue data enrolled in ATTACC (NCT01196130), a prospective genomic matching protocol utilizing paired tissue/ctDNA samples at baseline. We evaluated serial samples for RAS loss. 2) Using an external cohort of pts with mCRC and serial ctDNA with a targeted NGS assay sequencing all KRAS/ NRAS exons (Guardant360, Guardant Health), we screened pts for baseline RASMUT with no evidence of prior anti-EGFR exposure and evaluated for RAS loss. Results: 74 pts met criteria of RASMUT CRC with serial samples in ATTACC. Of these, 51 retained RASMUT. 22 pts had very low or absent levels of other clonal alterations such as APC or TP53 and are therefore unable to reliably detect RAS loss. One patient had true RAS loss with NRAS G13R, APC and TP53 mutations at baseline and persistent high-level APC and TP53 mutations without a detectable NRAS mutation, for an overall rate of RAS loss of 2% (1/52). In the second cohort we identified 162 pts, 34 of which had insufficient ctDNA to assess RAS loss on the serial sample as defined by loss of clonal alterations like APC and TP53. Of the remaining 128 patients, 11 had RAS loss (8.5%, with 1 NRAS, 10 KRAS). We next compared the relative mutant allele frequency (rMAF) between RAS retainers and RAS loss. The median baseline rMAF for pts who lost RAS was 0.74, compared to 0.86 in pts retaining RAS (p = 0.045). Conclusions: RAS reversion in mCRC from RASMUT to RASWT is uncommon and occurs at a rate between 2-8% in our two cohorts. RAS reversion is associated with a lower rMAF at baseline, suggesting subclonality. Liquid biopsies must be interpreted carefully, such that a determination of RAS mutation status is most informative in the presence of truncal APC and/or TP53 mutations.
5
Sheffels, Erin, and Robert L. Kortum. "The Role of Wild-Type RAS in Oncogenic RAS Transformation." Genes 12, no. 5 (April 28, 2021): 662. http://dx.doi.org/10.3390/genes12050662.
Full textAbstract:
The RAS family of oncogenes (HRAS, NRAS, and KRAS) are among the most frequently mutated protein families in cancers. RAS-mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that non-mutated wild-type (WT) RAS proteins play an important role in modulating downstream effector signaling and driving therapeutic resistance in RAS-mutated cancers. This modulation is complex as different WT RAS family members have opposing functions. The protein product of the WT RAS allele of the same isoform as mutated RAS is often tumor-suppressive and lost during tumor progression. In contrast, RTK-dependent activation of the WT RAS proteins from the two non-mutated WT RAS family members is tumor-promoting. Further, rebound activation of RTK–WT RAS signaling underlies therapeutic resistance to targeted therapeutics in RAS-mutated cancers. The contributions of WT RAS to proliferation and transformation in RAS-mutated cancer cells places renewed interest in upstream signaling molecules, including the phosphatase/adaptor SHP2 and the RasGEFs SOS1 and SOS2, as potential therapeutic targets in RAS-mutated cancers.
6
Roy, Sandrine, Bruce Wyse, and John F. Hancock. "H-Ras Signaling and K-Ras Signaling Are Differentially Dependent on Endocytosis." Molecular and Cellular Biology 22, no. 14 (July 15, 2002): 5128–40. http://dx.doi.org/10.1128/mcb.22.14.5128-5140.2002.
Full textAbstract:
ABSTRACT Endocytosis is required for efficient mitogen-activated protein kinase (MAPK) activation by activated growth factor receptors. We examined if H-Ras and K-Ras proteins, which are distributed across different plasma membrane microdomains, have equal access to the endocytic compartment and whether this access is necessary for downstream signaling. Inhibition of endocytosis by dominant interfering dynamin-K44A blocked H-Ras but not K-Ras-mediated PC12 cell differentiation and selectively inhibited H-Ras- but not K-Ras-mediated Raf-1 activation in BHK cells. H-Ras- but not K-Ras-mediated Raf-1 activation was also selectively dependent on phosphoinositide 3-kinase activity. Stimulation of endocytosis and endocytic recycling by wild-type Rab5 potentiated H-Ras-mediated Raf-1 activation. In contrast, Rab5-Q79L, which stimulates endocytosis but not endocytic recycling, redistributed activated H-Ras from the plasma membrane into enlarged endosomes and inhibited H-Ras-mediated Raf-1 activation. Rab5-Q79L expression did not cause the accumulation of wild-type H-Ras in enlarged endosomes. Expression of wild-type Rab5 or Rab5-Q79L increased the specific activity of K-Ras-activated Raf-1 but did not result in any redistribution of K-Ras from the plasma membrane to endosomes. These results show that H-Ras but not K-Ras signaling though the Raf/MEK/MAPK cascade requires endocytosis and endocytic recycling. The data also suggest a mechanism for returning Raf-1 to the cytosol after plasma membrane recruitment.
7
Wen, Zhi, and Jing Zhang. "Wild-Type Kras Inhibits NrasQ61R/+-Induced Leukemias." Blood 126, no. 23 (December 3, 2015): 1249. http://dx.doi.org/10.1182/blood.v126.23.1249.1249.
Full textAbstract:
Ras proteins belong to the super family of small GTPases. Although RAS mutations are oncogenic, it remains highly controversial whether wild-type (WT) RAS facilitates or inhibits tumorigenesis in the presence of oncogenic RAS. Previous studies suggest that this might depend on cell type, specific RAS isoforms, and/or stage of tumorigenesis (e.g. tumor initiation versus tumor progression). Recently, we found that deletion of WT Kras in oncogenic Kras mice promotes myeloidproliferative neoplasm (MPN) in a cell-autonomous manner. This is through promoting activation of all Ras isoforms and thus enhancing cytokine signaling in vivo. However, it remains unknown whether WT Kras plays a similar role in oncogenic Nras-induced leukemogenesis. To address this issue, we conditionally down-regulated WT Kras expression in a novel leukemia model induced by endogenous NrasQ61R/+. Detailed characterization of NrasQ61R allele reveals that NrasQ61R/+ displays an intermediate leukemogenic activity between NrasG12D/+ and NrasG12D/G12D. NrasQ61R/+ mice developed MPN (100%) and acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) (~10%) at the moribund stage with a median survival of 197 days. Therefore, NrasQ61R/+ mice provide an excellent experimental system to test genetic lesions promoting or inhibiting oncogenic Nras-induced leukemogenesis. We observed that 3-weeks after activation of NrasQ61R/+ and deletion of WT Kras, the double mutant mice displayed more severe MPN phenotypes than NrasQ61R/+ mice, as demonstrated by more prominent hepatosplenomegaly and further expanded myeloid compartment in bone marrow and spleen. Consistent with these MPN phenotypes, NrasQ61R/+; Kras-/- myeloid progenitor and precursor cells showed prolonged and hyperactivated GM-CSF signaling compared to NrasQ61R/+ cells. In addition, NrasQ61R/+; Kras-/- mice displayed further expanded common lymphoid progenitor compartment and a less differentiated phenotype in thymic T-cells than NrasQ61R/+ mice. In NrasQ61R/+; Kras-/- mice, early thymic T cell progenitors demonstrated enhanced cell proliferation and stronger ERK1/2 signaling compared to NrasQ61R/+ cells. Consequently, NrasQ61R/+; Kras-/- mice survived significantly shorter than NrasQ61R/+ mice (median survival: 97 days; P < 0.001) and 100% of them developed both MPN and T-ALL at the moribund stage. Preliminary results from bone marrow transplantation assay indicate that loss of WT Kras expression promoted NrasQ61R/+-induced MPN and T-ALL in a cell-autonomous manner. Taken together, our results suggest that loss of WT Kras promotes leukemogenesis in NrasQ61R/+ mice. We are currently studying on the underlying mechanisms. Disclosures No relevant conflicts of interest to declare.
8
Graham, S. M., A. B. Vojtek, S. Y. Huff, A. D. Cox, G. J. Clark, J. A. Cooper, and C. J. Der. "TC21 causes transformation by Raf-independent signaling pathways." Molecular and Cellular Biology 16, no. 11 (November 1996): 6132–40. http://dx.doi.org/10.1128/mcb.16.11.6132.
Full textAbstract:
Although the Ras-related protein TC21/R-Ras2 has only 55% amino acid identity with Ras proteins, mutated forms of TC21 exhibit the same potent transforming activity as constitutively activated forms of Ras. Therefore, like Ras, TC21 may activate signaling pathways that control normal cell growth and differentiation. To address this possibility, we determined if regulators and effectors of Ras are also important for controlling TC21 activity. First, we determined that Ras guanine nucleotide exchange factors (SOS1 and RasGRF/CDC25) synergistically enhanced wild-type TC21 activity in vivo and that Ras GTPase-activating proteins (GAPs; p120-GAP and NF1-GAP) stimulated wild-type TC21 GTP hydrolysis in vitro. Thus, extracellular signals that activate Ras via SOS1 activation may cause coordinate activation of Ras and TC21. Second, we determined if Raf kinases were effectors for TC21 transformation. Unexpectedly, yeast two-hybrid binding analyses showed that although both Ras and TC21 could interact with the isolated Ras-binding domain of Raf-1, only Ras interacted with full-length Raf-1, A-Raf, or B-Raf. Consistent with this observation, we found that Ras- but not TC21-transformed NIH 3T3 cells possessed constitutively elevated Raf-1 and B-Raf kinase activity. Thus, Raf kinases are effectors for Ras, but not TC21, signaling and transformation. We conclude that common upstream signals cause activation of Ras and TC21, but activated TC21 controls cell growth via distinct Raf-independent downstream signaling pathways.
9
Dent, P., D. B. Reardon, D. K. Morrison, and T. W. Sturgill. "Regulation of Raf-1 and Raf-1 mutants by Ras-dependent and Ras-independent mechanisms in vitro." Molecular and Cellular Biology 15, no. 8 (August 1995): 4125–35. http://dx.doi.org/10.1128/mcb.15.8.4125.
Full textAbstract:
The serine/threonine kinase Raf-1 functions downstream from Ras to activate mitogen-activated protein kinase kinase, but the mechanisms of Raf-1 activation are incompletely understood. To dissect these mechanisms, wild-type and mutant Raf-1 proteins were studied in an in vitro system with purified plasma membranes from v-Ras- and v-Src-transformed cells (transformed membranes). Wild-type (His)6- and FLAG-Raf-1 were activated in a Ras- and ATP-dependent manner by transformed membranes; however, Raf-1 proteins that are kinase defective (K375M), that lack an in vivo site(s) of regulatory tyrosine (YY340/341FF) or constitutive serine (S621A) phosphorylation, that do not bind Ras (R89L), or that lack an intact zinc finger (CC165/168SS) were not. Raf-1 proteins lacking putative regulatory sites for an unidentified kinase (S259A) or protein kinase C (S499A) were activated but with apparently reduced efficiency. The kinase(s) responsible for activation by Ras or Src may reside in the plasma membrane, since GTP loading of plasma membranes from quiescent NIH 3T3 cells (parental membranes) induced de novo capacity to activate Raf-1. Wild-type Raf-1, possessing only basal activity, was not activated by parental membranes in the absence of GTP loading. In contrast, Raf-1 Y340D, possessing significant activity, was, surprisingly, stimulated by parental membranes in a Ras-independent manner. The results suggest that activation of Raf-1 by phosphorylation may be permissive for further modulation by another membrane factor, such as a lipid. A factor(s) extracted with methanol-chloroform from transformed membranes or membranes from Sf9 cells coexpressing Ras and SrcY527F significantly enhanced the activity of Raf-1 Y340D or active Raf-1 but not that of inactive Raf-1. Our findings suggest a model for activation of Raf-1, wherein (i) Raf-1 associates with Ras-GTP, (ii) Raf-1 is activated by tyrosine and/or serine phosphorylation, and (iii) Raf-1 activity is further increased by a membrane cofactor.
10
Tang, Y., Z. Chen, D. Ambrose, J. Liu, J. B. Gibbs, J. Chernoff, and J. Field. "Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts." Molecular and Cellular Biology 17, no. 8 (August 1997): 4454–64. http://dx.doi.org/10.1128/mcb.17.8.4454.
Full textAbstract:
Among the mechanisms by which the Ras oncogene induces cellular transformation, Ras activates the mitogen-activated protein kinase (MAPK or ERK) cascade and a related cascade leading to activation of Jun kinase (JNK or SAPK). JNK is additionally regulated by the Ras-related G proteins Rac and Cdc42. Ras also regulates the actin cytoskeleton through an incompletely elucidated Rac-dependent mechanism. A candidate for the physiological effector for both JNK and actin regulation by Rac and Cdc42 is the serine/threonine kinase Pak (p65pak). We show here that expression of a catalytically inactive mutant Pak, Pak1(R299), inhibits Ras transformation of Rat-1 fibroblasts but not of NIH 3T3 cells. Typically, 90 to 95% fewer transformed colonies were observed in cotransfection assays with Rat-1 cells. Pak1(R299) did not inhibit transformation by the Raf oncogene, indicating that inhibition was specific for Ras. Furthermore, Rat-1 cell lines expressing Pak1(R299) were highly resistant to Ras transformation, while cells expressing wild-type Pak1 were efficiently transformed by Ras. Pak1(L83,L86,R299), a mutant that fails to bind either Rac or Cdc42, also inhibited Ras transformation. Rac and Ras activation of JNK was inhibited by Pak1(R299) but not by Pak1(L83,L86,R299). Ras activation of ERK was inhibited by both Pak1(R299) and Pak1(L83,L86,R299), while neither mutant inhibited Raf activation of ERK. These results suggest that Pak1 interacts with components essential for Ras transformation and that inhibition can be uncoupled from JNK but not ERK signaling.
11
Hayes, Tikvah K., and Channing J. Der. "Mutant and Wild-type Ras: Co-conspirators in Cancer." Cancer Discovery 3, no. 1 (January 2013): 24–26. http://dx.doi.org/10.1158/2159-8290.cd-12-0521.
Full text
12
Zhou, Bingying, Channing J. Der, and Adrienne D. Cox. "The role of wild type RAS isoforms in cancer." Seminars in Cell & Developmental Biology 58 (October 2016): 60–69. http://dx.doi.org/10.1016/j.semcdb.2016.07.012.
Full text
13
LI, Xiaomei, Vicki VAN PUTTEN, Fariba ZARINETCHI, E. Michael NICKS, Seth THALER, E. Lynn HEASLEY, and A. Raphael NEMENOFF. "Suppression of smooth-muscle α-actin expression by platelet-derived growth factor in vascular smooth-muscle cells involves Ras and cytosolic phospholipase A2." Biochemical Journal 327, no. 3 (November 1, 1997): 709–16. http://dx.doi.org/10.1042/bj3270709.
Full textAbstract:
Platelet-derived growth factor (PDGF), which is a potent mitogen for vascular smooth-muscle cells (VSMC), also inhibits the expression of specific smooth-muscle proteins, including smooth-muscle α-actin (SM-α-actin), in these cells. The goal of this study was to identify signalling pathways mediating these distinct effects. In rat aortic VSMC, PDGF caused a rapid activation of Ras and Raf, leading to the activation of mitogen-activated protein kinases (ERKs). Cells stably transfected with constitutively active Ras (H-Ras) expressed low levels of SM-α-actin protein. Arginine vasopressin, which stimulated SM-α-actin promoter activity in wild-type cells or controls (Neo; transfected with a plasmid lacking an insert), failed to do so in cells transiently expressing H-Ras. The effects of Ras on suppression of SM-α-actin expression were not mediated by the Raf/ERK pathway, since cells stably expressing constitutively active Raf (BxB-Raf) had normal levels of SM-α-actin protein, and stimulation of SM-α-actin promoter activity by vasopressin was unaffected in cells transiently expressing BxB-Raf. Furthermore a specific inhibitor of ERK activation had no effect on SM-α-actin expression. Exposure of wild-type VSMC to PDGF, or stable expression of Ras but not Raf, also resulted in constitutive increases in prostaglandin E2 production and cytosolic phospholipase A2 (cPLA2) activity, which was mediated by an increased expression of cPLA2 protein. Transient expression of cPLA2 in wild-type VSMC inhibited the stimulation of SM-α-actin promoter activity by vasopressin. These results suggest that PDGF-induced inhibition of SM-α-actin expression is mediated through a Ras-dependent/Raf independent pathway involving the induction of cPLA2 and eicosanoid production.
14
Randall, Jamie, Hongkun Wang, Sheryl Krevsky Elkin, Gail Payne, Sarah Mullaly, Erica Marchlik, Dan Barnett, et al. "Targetable mutations in gastrointestinal malignancies: A comparison of RAS mutant and RAS wild type tumors." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 129. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.129.
Full textAbstract:
129 Background: KRAS and NRAS (RAS) mutations are considered driver mutations in gastrointestinal malignancies such as colorectal and pancreatic cancer. Our institution obtains broad molecular testing (commercial panels with full exon coverage of at least 300 genes) for all stage IV gastrointestinal malignancies that are reviewed at an internal molecular tumor board (MTB). The MTB subjectively felt there was less benefit from comprehensive molecular testing in RAS mutant tumors and wished to quantify this using standardized analysis according to validated guidelines. Methods: We performed a retrospective cohort study of 209 consecutive genomic sequencing results of advanced gastrointestinal malignancies at our institution dating from March 2016 until December 2019. We compared the number of “targetable” mutations in the RAS mutant and wild type (WT) malignancies, as analyzed by an interpretation service according to the Association of Molecular Pathology (AMP) guidelines. A lower AMP score corresponds to a higher level of evidence as a predictive biomarker. We also compared molecular tumor board specific recommendations for each group (excluding recommendations regarding RAS such as EGFR mAbs). Results: There were 134 RAS mutant and 75 RAS WT cases. Alterations with AMP scores of 1A,1B, and 1C were more commonly seen in the RAS WT population 18/75 and 9/134 respectively (24.0% versus 6.7% p-value=0.0004). 39 of 75 cases in RAS WT and 27/134 in RAS mutant (52.0 versus 20.1%, p-value <0.0001) cohort had at least one alteration that was deemed actionable by our institution’s current MTB criteria. Conclusions: Actionable mutations were significantly less common in the RAS mutant versus RAS WT population, and further studies assessing the value of comprehensive genomic testing in RAS mutant gastrointestinal malignancies may be warranted. [Table: see text]
15
Ikonomou, Georgia, Vassiliki Kostourou, Senji Shirasawa, Takehiko Sasazuki, Martina Samiotaki, and George Panayotou. "Interplay between oncogenic K-Ras and wild-type H-Ras in Caco2 cell transformation." Journal of Proteomics 75, no. 17 (September 2012): 5356–69. http://dx.doi.org/10.1016/j.jprot.2012.06.038.
Full text
16
Finlay, C. A. "The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth." Molecular and Cellular Biology 13, no. 1 (January 1993): 301–6. http://dx.doi.org/10.1128/mcb.13.1.301-306.1993.
Full textAbstract:
Expression of a p53-associated protein, Mdm-2 (murine double minute-2), can inhibit p53-mediated transactivation. In this study, overexpression of the Mdm-2 protein was found to result in the immortalization of primary rat embryo fibroblasts (REFs) and, in conjunction with an activated ras gene, in the transformation of REFs. The effect of wild-type p53 on the transforming properties of mdm-2 was determined by transfecting REFs with ras, mdm-2, and normal p53 genes. Transfection with ras plus mdm-2 plus wild-type p53 resulted in a 50% reduction in the number of transformed foci (relative to the level for ras plus mdm-2); however, more than half (9 of 17) of the cell lines derived from these foci expressed low levels of a murine p53 protein with the characteristics of a wild-type p53. These results are in contrast to previous studies which demonstrated that even minimal levels of wild-type p53 are not tolerated in cells transformed by ras plus myc, E1A, or mutant p53. The mdm-2 oncogene can overcome the previously demonstrated growth-suppressive properties of p53.
17
Finlay, C. A. "The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth." Molecular and Cellular Biology 13, no. 1 (January 1993): 301–6. http://dx.doi.org/10.1128/mcb.13.1.301.
Full textAbstract:
Expression of a p53-associated protein, Mdm-2 (murine double minute-2), can inhibit p53-mediated transactivation. In this study, overexpression of the Mdm-2 protein was found to result in the immortalization of primary rat embryo fibroblasts (REFs) and, in conjunction with an activated ras gene, in the transformation of REFs. The effect of wild-type p53 on the transforming properties of mdm-2 was determined by transfecting REFs with ras, mdm-2, and normal p53 genes. Transfection with ras plus mdm-2 plus wild-type p53 resulted in a 50% reduction in the number of transformed foci (relative to the level for ras plus mdm-2); however, more than half (9 of 17) of the cell lines derived from these foci expressed low levels of a murine p53 protein with the characteristics of a wild-type p53. These results are in contrast to previous studies which demonstrated that even minimal levels of wild-type p53 are not tolerated in cells transformed by ras plus myc, E1A, or mutant p53. The mdm-2 oncogene can overcome the previously demonstrated growth-suppressive properties of p53.
18
Vidimar, Vania, Greg L. Beilhartz, Minyoung Park, Marco Biancucci, Matthew B. Kieffer, David R. Gius, Roman A. Melnyk, and Karla J. F. Satchell. "An engineered chimeric toxin that cleaves activated mutant and wild-type RAS inhibits tumor growth." Proceedings of the National Academy of Sciences 117, no. 29 (July 2, 2020): 16938–48. http://dx.doi.org/10.1073/pnas.2000312117.
Full textAbstract:
Despite nearly four decades of effort, broad inhibition of oncogenic RAS using small-molecule approaches has proven to be a major challenge. Here we describe the development of a pan-RAS biologic inhibitor composed of the RAS-RAP1–specific endopeptidase fused to the protein delivery machinery of diphtheria toxin. We show that this engineered chimeric toxin irreversibly cleaves and inactivates intracellular RAS at low picomolar concentrations terminating downstream signaling in receptor-bearing cells. Furthermore, we demonstrate in vivo target engagement and reduction of tumor burden in three mouse xenograft models driven by either wild-type or mutantRAS. Intracellular delivery of a potent anti-RAS biologic through a receptor-mediated mechanism represents a promising approach to developing RAS therapeutics against a broad array of cancers.
19
Nevala-Plagemann, Christopher, Siddharth Iyengar, Andrew D. Trunk, Lisa Pappas, Benjamin Haaland, and Ignacio Garrido-Laguna. "Treatment Trends and Clinical Outcomes of Left-Sided RAS/RAF Wild-Type Metastatic Colorectal Cancer in the United States." Journal of the National Comprehensive Cancer Network 20, no. 3 (March 2022): 268–75. http://dx.doi.org/10.6004/jnccn.2021.7079.
Full textAbstract:
Background: Post hoc analysis of the CALGB/SWOG 80405 trial suggests that anti-EGFR therapy may be superior to bevacizumab when added to first-line chemotherapy in patients with metastatic colorectal cancer (mCRC) who have left-sided primary tumors. We evaluated trends in use of anti-EGFR agents in patients with left-sided RAS/RAF wild-type (WT) mCRC and compared clinical outcomes among the most commonly used treatment strategies. Methods: A nationwide electronic health record (EHR)–derived deidentified database was reviewed for patients with left-sided RAS/RAF WT mCRC. Treatment trends over time were assessed by fitting a linear model to the percentage of patients receiving anti-EGFR therapy. A propensity score weighted Cox model was used to compare overall survival (OS) stratified by first-line targeted therapy received. Results: A total of 1,607 patients with left-sided RAS/RAF WT mCRC received standard first-line chemotherapy. Of these, 965 (60%) received bevacizumab and 186 (12%) received an anti-EGFR agent. The percentage of patients receiving an anti-EGFR increased from 9% in 2013 to 16% in 2018. Median OS for patients treated with chemotherapy alone was 27.3 months (95% CI, 24.8–32.3), 27.5 months with bevacizumab (95% CI, 25.8–28.9; hazard ratio [HR], 0.88; P=.33), and 42.9 months with an anti-EGFR agent (95% CI, 36.0 to not reached; HR, 0.52; P=.005). Conclusions: This analysis suggests that chemotherapy with bevacizumab remained the most widely used first-line treatment strategy for patients with left-sided RAS/RAF WT mCRC in the United States in 2018. Despite this preference, treatment with an anti-EGFR agent was associated with improved OS.
20
Shang, Xun, Lina Li, Jose Concelas, Fukun Guo, Deidre Daria, Hartmut Geiger, Nancy Ratner, and Yi Zheng. "R-Ras Regulates Hematopoietic Stem/Progenitor Cell Adhesion, Migration, and Mobilization through Rac GTPase-Mediated Signals." Blood 110, no. 11 (November 16, 2007): 221. http://dx.doi.org/10.1182/blood.v110.11.221.221.
Full textAbstract:
Abstract Hematopoietic stem/progenitor cells (HSPCs) are maintained by strictly regulated signals in the bone marrow microenvironment. One challenge in understanding the complex mode of HSPC regulation is to link intracellular signal components with extracellular stimuli. R-Ras is a member of the Ras family small GTPases. Previous mouse genetic studies suggest that R-Ras mRNA is primarily expressed in endothelial cells and R-Ras is involved in vascular angiogenesis. In clonal cell lines, although dominant mutant overexpression studies suggest a possible role of R-Ras in regulating cell adhesion and spreading, proliferation and/or differentiation in a cell-type dependent manner, it remains controversial whether R-Ras activity may promote or inhibit cell adhesion and migration. Here, in a mouse knockout model, we have examined the role of R-Ras in HSPC regulation by a combined in vivo and in vitro approach. Firstly, we found that R-Ras is expressed in the Lin− low density bone marrow cells of wild-type mice, and R-Ras activity in the cells is downregulated by cytokines and chemokines such as SCF and SDF-1a (∼ 20% and 40% of unstimulated control, respectively). Secondly, R-Ras deficiency did not significantly affect peripheral blood CBC, nor alter the frequency or distribution of long-term and short-term hematopoietic stem cells (defined by IL7Ra−Lin−Sca-1+c-Kit+CD34− and IL7Ra−Lin−Sca-1+c-Kit+CD34+ genotypes, respectively) in the bone marrow, peripheral blood and spleen. Competitive repopulation experiments using the wild-type and R-Ras−/− bone marrow cells at 1:1 ratio in lethally irradiated recipient mice showed no significant difference of blood cells of the two genotypes in the recipients up to 6 months post-transplantation. R-Ras−/− bone marrow cells did not show a detectable difference in colony forming unit activities assayed in the presence of various combinations of SCF, TPO, EPO, IL3, G-CSF and serum, compared with the matching wild-type cells. Thirdly, upon challenge with G-CSF, a HSPC mobilizing agent, R-Ras−/− mice demonstrated a markedly enhanced ability to mobilize HSPCs from bone marrow to peripheral blood as revealed by genotypic and colony-forming unit analyses (WT: 150 vs. KO: 320 per 200uL blood, p=0.018), and R-Ras−/− HSPCs exhibit significantly decreased homing activity (WT: 4.3% vs. KO: 2.8%, p<0.001). Fourthly, isolated R-Ras−/− HSPCs displayed a constitutively assembled cortical actin cytoskeleton structure in the absence of cytokine or chemokine stimulation, similar to that of activated wild-type HSPCs. The R-Ras−/− HSPCs were defective in adhesion of cobblestone area-forming cells to a bone marrow-derived stroma cell line (FBMD-1) and in adhesion to fibronectin CH296 fragment, and showed a drastically increased ability to migrate toward a SDF-1a gradient (WT: 16% vs. KO: 38%, p<0.001). These data point to a HSPC-intrinsic role of R-Ras in adhesion and migration. Finally, the functional changes of R-Ras−/− cells were associated with a ∼3 fold increase in Rac-GTP species and constitutively elevated Rac downstream signals of phsopho-PAK1 and phospho-myosin light chain. Partial inhibition of Rac activity by NSC23766, a Rac GTPase-specific inhibitor, readily reversed the migration phenotype under SDF-1a stimulation. Taken together, these studies demonstrate that R-Ras is a critical signal regulator for HSPC adhesion, homing, migration, and mobilization through a mechanism involving Rac GTPase-regulated cytoskeleton and adhesion machinery.
21
Nicolazzo, Chiara, Ludovic Barault, Salvatore Caponnetto, Marco Macagno, Gianluigi De Renzi, Angela Gradilone, Francesca Belardinilli, Enrico Cortesi, Federica Di Nicolantonio, and Paola Gazzaniga. "Circulating Methylated DNA to Monitor the Dynamics of RAS Mutation Clearance in Plasma from Metastatic Colorectal Cancer Patients." Cancers 12, no. 12 (December 4, 2020): 3633. http://dx.doi.org/10.3390/cancers12123633.
Full textAbstract:
The clearance of RAS mutations in plasma circulating tumor DNA (ctDNA) from originally RAS-mutant metastatic colorectal cancer (mCRC) has been recently demonstrated. Clinical trials investigating whether RAS mutant mCRC who “convert” to wild-type in plasma might benefit from EGFR blockade are ongoing. Detection of tumor-specific DNA methylation alterations in ctDNA has been suggested as a specific tool to confirm the tumoral origin of cell-free DNA. We monitored RAS clearance in plasma from patients with RAS-mutant mCRC at baseline (pre-treatment) (T0); after 4 months of first-line therapy (T1); at the time of first (T2) and second (T3) progression. A five-gene methylation panel was used to confirm the presence of ctDNA in samples in which RAS mutation clearance was detected. At T1, ctDNA analysis revealed wild-type RAS status in 83% of samples, all not methylated, suggesting at this time point the lack of ctDNA shedding. At T2, ctDNA analysis revealed wild-type RAS status in 83% of samples, of which 62.5% were found methylated. At T3, 50% of wild-type RAS samples were found methylated. Non-methylated samples were found in patients with lung or brain metastases. This five-gene methylation test might be useful to confirm the presence of ctDNA in RAS wild-type plasma samples.
22
Li, Willis X., Herve Agaisse, Bernard Mathey-Prevot, and Norbert Perrimon. "Differential requirement for STAT by gain-of-function and wild-type receptor tyrosine kinase Torso in Drosophila." Development 129, no. 18 (September 15, 2002): 4241–48. http://dx.doi.org/10.1242/dev.129.18.4241.
Full textAbstract:
Malignant transformation frequently involves aberrant signaling from receptor tyrosine kinases (RTKs). These receptors commonly activate Ras/Raf/MEK/MAPK signaling but when overactivated can also induce the JAK/STAT pathway, originally identified as the signaling cascade downstream of cytokine receptors. Inappropriate activation of STAT has been found in many human cancers. However, the contribution of the JAK/STAT pathway in RTK signaling remains unclear. We have investigated the requirement of the JAK/STAT pathway for signaling by wild-type and mutant forms of the RTK Torso (Tor) using a genetic approach in Drosophila. Our results indicate that the JAK/STAT pathway plays little or no role in signaling by wild-type Tor. In contrast, we find that STAT, encoded by marelle (mrl; DStat92E), is essential for the gain-of-function mutant Tor (TorGOF) to activate ectopic gene expression. Our findings indicate that the Ras/Raf/MEK/MAPK signaling pathway is sufficient to mediate the normal functions of wild-type RTK, whereas the effects of gain-of-function mutant RTK additionally require STAT activation.
23
Shibayama, Hirohiko, Naoyuki Anzai, Stephen E. Braun, Seiji Fukuda, Charlie Mantel, and Hal E. Broxmeyer. "H-Ras Is Involved in the Inside-out Signaling Pathway of Interleukin-3–Induced Integrin Activation." Blood 93, no. 5 (March 1, 1999): 1540–48. http://dx.doi.org/10.1182/blood.v93.5.1540.
Full textAbstract:
Abstract The proto-oncogene product, p21ras, has been implicated in the cellular mechanism of adhesion, although its precise role has been controversial. Numerous cytokines and growth-factors activate Ras, which is an important component of their growth-promoting signaling pathways. On the other hand, the role of Ras in cytokine-induced adhesion has not been elucidated. We therefore investigated the function of H-Ras in the inside-out signaling pathway of interleukin-3 (IL-3)–induced integrin activation in the murine Baf3 cell line after transfection of cells with either constitutively active, dominant-negative, or wild-type H-Ras cDNAs. Adhesion of Baf3 cells to fibronectin was induced by IL-3 in a dose-dependent manner via very late antigen-4 (VLA-4; 4β1 integrins) and VLA-5 (5β1 integrins) activation. On the other hand, IL-4 did not induce the adhesion of Baf3 cells to fibronectin, although IL-4 did stimulate the cell proliferation of Baf3 cells. Constitutively active H-Ras–transfected Baf3 cells adhered to fibronectin without IL-3 stimulation through VLA-4 and VLA-5, whereas dominant-negative H-Ras–transfected Baf3 cells showed significantly less adhesion induced by IL-3 compared with wild-type and constitutively active H-Ras–transfected Baf3 cells. Anti-β1 integrin antibody (clone; 9EG7), which is known to change integrin conformation and activate integrins, induced the adhesion of dominant-negative H-Ras–transfected Baf3 cells as much as the other types of H-Ras–transfected Baf3 cells. 8-Br-cAMP, Dibutyryl-cAMP, Ras-Raf-1 pathway inhibitors, and PD98059, a MAPK kinase inhibitor, suppressed proliferation and phosphorylation of MAPK detected by Western blotting with anti–phospho-MAPK antibody, but not adhesion of any type of H-Ras–transfected Baf3 cells, whereas U-73122, a phospholipase C (PLC) inhibitor, suppressed adhesion of these cells completely. These data indicate that H-Ras and PLC, but not Raf-1, MAPK kinase, or the MAPK pathway, are involved in the inside-out signaling pathway of IL-3–induced VLA-4 and VLA-5 activation in Baf3 cells.
24
Shibayama, Hirohiko, Naoyuki Anzai, Stephen E. Braun, Seiji Fukuda, Charlie Mantel, and Hal E. Broxmeyer. "H-Ras Is Involved in the Inside-out Signaling Pathway of Interleukin-3–Induced Integrin Activation." Blood 93, no. 5 (March 1, 1999): 1540–48. http://dx.doi.org/10.1182/blood.v93.5.1540.405k10_1540_1548.
Full textAbstract:
The proto-oncogene product, p21ras, has been implicated in the cellular mechanism of adhesion, although its precise role has been controversial. Numerous cytokines and growth-factors activate Ras, which is an important component of their growth-promoting signaling pathways. On the other hand, the role of Ras in cytokine-induced adhesion has not been elucidated. We therefore investigated the function of H-Ras in the inside-out signaling pathway of interleukin-3 (IL-3)–induced integrin activation in the murine Baf3 cell line after transfection of cells with either constitutively active, dominant-negative, or wild-type H-Ras cDNAs. Adhesion of Baf3 cells to fibronectin was induced by IL-3 in a dose-dependent manner via very late antigen-4 (VLA-4; 4β1 integrins) and VLA-5 (5β1 integrins) activation. On the other hand, IL-4 did not induce the adhesion of Baf3 cells to fibronectin, although IL-4 did stimulate the cell proliferation of Baf3 cells. Constitutively active H-Ras–transfected Baf3 cells adhered to fibronectin without IL-3 stimulation through VLA-4 and VLA-5, whereas dominant-negative H-Ras–transfected Baf3 cells showed significantly less adhesion induced by IL-3 compared with wild-type and constitutively active H-Ras–transfected Baf3 cells. Anti-β1 integrin antibody (clone; 9EG7), which is known to change integrin conformation and activate integrins, induced the adhesion of dominant-negative H-Ras–transfected Baf3 cells as much as the other types of H-Ras–transfected Baf3 cells. 8-Br-cAMP, Dibutyryl-cAMP, Ras-Raf-1 pathway inhibitors, and PD98059, a MAPK kinase inhibitor, suppressed proliferation and phosphorylation of MAPK detected by Western blotting with anti–phospho-MAPK antibody, but not adhesion of any type of H-Ras–transfected Baf3 cells, whereas U-73122, a phospholipase C (PLC) inhibitor, suppressed adhesion of these cells completely. These data indicate that H-Ras and PLC, but not Raf-1, MAPK kinase, or the MAPK pathway, are involved in the inside-out signaling pathway of IL-3–induced VLA-4 and VLA-5 activation in Baf3 cells.
25
Powers, S., K. O'Neill, and M. Wigler. "Dominant yeast and mammalian RAS mutants that interfere with the CDC25-dependent activation of wild-type RAS in Saccharomyces cerevisiae." Molecular and Cellular Biology 9, no. 2 (February 1989): 390–95. http://dx.doi.org/10.1128/mcb.9.2.390-395.1989.
Full textAbstract:
Two mutant alleles of RAS2 were discovered that dominantly interfere with wild-type RAS function in the yeast Saccharomyces cerevisiae. An amino acid substitution which caused the dominant interference was an alanine for glycine at position 22 or a proline for alanine at position 25. Analogous mutations in human H-ras also dominantly inhibited RAS function when expressed in yeast cells. The inhibitory effects of the mutant RAS2 or H-ras genes could be overcome by overexpression of CDC25, but only in the presence of wild-type RAS. These results suggest that these mutant RAS genes interfere with the normal interaction of RAS and CDC25 proteins and suggest that this interaction is direct and has evolutionarily conserved features.
26
Powers, S., K. O'Neill, and M. Wigler. "Dominant yeast and mammalian RAS mutants that interfere with the CDC25-dependent activation of wild-type RAS in Saccharomyces cerevisiae." Molecular and Cellular Biology 9, no. 2 (February 1989): 390–95. http://dx.doi.org/10.1128/mcb.9.2.390.
Full textAbstract:
Two mutant alleles of RAS2 were discovered that dominantly interfere with wild-type RAS function in the yeast Saccharomyces cerevisiae. An amino acid substitution which caused the dominant interference was an alanine for glycine at position 22 or a proline for alanine at position 25. Analogous mutations in human H-ras also dominantly inhibited RAS function when expressed in yeast cells. The inhibitory effects of the mutant RAS2 or H-ras genes could be overcome by overexpression of CDC25, but only in the presence of wild-type RAS. These results suggest that these mutant RAS genes interfere with the normal interaction of RAS and CDC25 proteins and suggest that this interaction is direct and has evolutionarily conserved features.
27
Strickler, John H., Christel N. Rushing, Hope E. Uronis, Michael A. Morse, Donna Niedzwiecki, Gerard C. Blobe, Ashley N. Moyer, et al. "Cabozantinib and Panitumumab for RAS Wild‐Type Metastatic Colorectal Cancer." Oncologist 26, no. 6 (February 9, 2021): 465. http://dx.doi.org/10.1002/onco.13678.
Full text
28
Lin, Yi-Jang, and Kevin M. Haigis. "Brother’s Keeper: Wild-Type Mutant K-Ras Dimers Limit Oncogenesis." Cell 172, no. 4 (February 2018): 645–47. http://dx.doi.org/10.1016/j.cell.2018.01.019.
Full text
29
Bai, Yuru, Lu Qiao, Ning Xie, Yan Li, Yongzhan Nie, Yan Pan, Yupeng Shi, Jinhai Wang, and Na Liu. "TOB1 suppresses proliferation in K‐Ras wild‐type pancreatic cancer." Cancer Medicine 9, no. 4 (December 31, 2019): 1503–14. http://dx.doi.org/10.1002/cam4.2756.
Full text
30
Yoshinami, Yuri, Hiroki Osumi, Atsuo Takashima, Ryoichi Sawada, Kota Ouchi, Takeru Wakatsuki, Akira Ooki, et al. "A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 206. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.206.
Full textAbstract:
206 Background: The ’’Neo RAS’’ phenomenon, in which tissue rat sarcoma viral oncogene homolog ( RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because epidermal growth factor receptor (EGFR) inhibitors, which were originally considered to be ineffective, may converted to be effective. This multi-center study investigated its incidence and clinicopathological characteristics that are still unclear. Methods: 107 mCRC patients with tissue RAS MT, confirmed using MEBGEN RASKET-B, who were refractory or intolerant to previous chemotherapies, including fluoropyrimidines, oxaliplatin, or irinotecan were enrolled in 4 institutions from June 2021 to August 2022. The RAS status in ctDNA was investigated after prior chemotherapy using ONCOBEAMTM RAC CRC. Clinicopathological characteristics were compared between patients with RAS MT and RAS WT (Neo RAS) in ctDNA. Results: The incidence of Neo RAS WT mCRC was 21.5% (23/107). The frequency of Neo RAS in KRAS exon 2 was significantly lower than that in other alleles such as exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). There were significant differences in frequency of Neo RAS between male vs female (30.6% [19/62] vs 8.9% [4/45], P = 0.008), absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001), and between two groups divided at the median: tumor diameter (> 60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), carcinoembryonic antigen level (> 38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), carbohydrate antigen 19-9 level (> 158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). Logistic regression multivariate analysis, absence of liver metastasis (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012) and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the appearance of Neo RAS WT mCRC. Conclusions: Original RAS status in tissue, tumor diameter and liver metastasis are related to conversion to Neo RAS WT mCRC.
31
Malumbres, Marcos, Ignacio Pérez De Castro, María I. Hernández, María Jiménez, Teresa Corral, and Angel Pellicer. "Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b." Molecular and Cellular Biology 20, no. 8 (April 15, 2000): 2915–25. http://dx.doi.org/10.1128/mcb.20.8.2915-2925.2000.
Full textAbstract:
ABSTRACT The cell cycle inhibitor p15 INK4b is frequently inactivated by homozygous deletion together with p16 INK4a and p19 ARF in some types of tumors. Although the tumor suppressor capability of p15 INK4b is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16 INK4a alterations. Here we show that, in vitro, p15 INK4b is a strong inhibitor of cellular transformation by Ras. Surprisingly, p15 INK4b is induced in cultured cells by oncogenic Ras to an extent similar to that of p16 INK4a , and their expression is associated with premature G1 arrest and senescence. Ras-dependent induction of these two INK4 genes is mediated mainly by the Raf-Mek-Erk pathway. Studies with activated and dominant negative forms of Ras effectors indicate that the Raf-Mek-Erk pathway is essential for induction of both the p15 INK4b and p16 INK4a promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response. Our results indicate that p15 INK4b , by itself, is able to stop cell transformation by Ras and other oncogenes such as Rgr (a new oncogene member of the Ral-GDS family, whose action is mediated through Ras). In fact, embryonic fibroblasts isolated from p15 INK4b knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15 INK4b -deficient mouse embryo fibroblasts are more sensitive than wild-type cells to transformation by a combination of the Rgr and E1A oncogenes. The cell cycle inhibitor p15 INK4b is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.
32
Luderus, M. E., C. D. Reymond, P. J. Van Haastert, and R. Van Driel. "Expression of a mutated ras gene in Dictyostelium discoideum alters the binding of cyclic AMP to its chemotactic receptor." Journal of Cell Science 90, no. 4 (August 1, 1988): 701–6. http://dx.doi.org/10.1242/jcs.90.4.701.
Full textAbstract:
Dictyostelium discoideum cells contain a ras gene that codes for a polypeptide that is highly homologous to the human ras proteins. Extra copies of the wild-type gene or a gene carrying a missense mutation in codon 12 (ras-Gly12 and ras-Thr12, respectively) have been introduced into Dictyostelium cells by transformation. We have investigated the properties of the chemotactic cell surface cyclic AMP receptor in crude membrane preparations of wild-type Dictyostelium cells and ras-Gly12 and ras-Thr12 transformants. In vitro, an ATP- and Ca2+-dependent reduction of the number of cyclic AMP receptors was observed in membranes from all three cell types. The number of available receptors was decreased maximally by about 50%. In the presence of ATP the half-maximal Ca2+ concentration required for this process was about 10(−5) M in wild-type and ras-Gly12 membranes, and less than 10(−7) M in ras-Thr12 membranes. Addition of GTP (but not GDP) or the phorbol ester PMA (phorbol-12-myristate-13-acetate) reduced the Ca2+ requirement of the process in wild-type and ras-Gly12 membranes to the physiological level of less than 10(−7) M. In membranes derived from ras-Thr12 cells addition of GTP or PMA had no effect. The results indicate that D. discoideum cells contain a cyclic AMP receptor-controlling pathway that can be activated in vitro and involves a GTP-binding protein and a Ca2+ plus ATP-dependent activity, possibly protein kinase C. It is concluded that the ras protein specifically interacts with this pathway; the pathway appears to be constitutively activated by the mutated ras gene product.
33
George, Ben, Joel R. Greenbowe, Andrew Eugene Hendifar, Talia Golan, Milind M. Javle, Anirban Maitra, Nathan Bahary, et al. "Comprehensive genomic profiling (CGP) in KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC)." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 271. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.271.
Full textAbstract:
271 Background: Mutations in oncogenic KRAS have been widely accepted as the signature genomic alteration (GA) in sporadic PDAC, but therapeutic efforts aimed at targeting constitutively activated KRAS have been disappointing. We examined somatic GAs in KRAS WT PDAC utilizing a CGP platform to identify actionable targets. Methods: DNA was extracted from formalin fixed paraffin embedded (FFPE) PDAC clinical specimens and CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads. Alterations in the RAS/ RAF/ MEK pathway genes ( KRAS, NRAS, HRAS, ARF, BRAF, EGFR, MAP2K2, MAP2K1, MAPK1) and DNA Damage Repair (DDR) pathway genes ( BRCA1/2, ATM, ATR, BRIP1, RAD50, RAD51, RAD52, PALB2, CHEK1, CHEK2) were examined. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. TMB was categorized based on mutations(m)/Mbp of DNA - high (H; > 20), Intermediate (I; 8-20) and low (L; < 8). Results: CGP was performed on 3426 PDAC specimens; 1815 (53%) were male, 390 (11.3%) were KRAS WT. GAs in the RAS/ RAF/ MEK pathway were identified in 90.6% of all cases, while 68 (17.4%) KRAS WT cases had one or more GAs in RAS/ RAF/ MEK pathway genes. DDR pathway GAs were identified in 1405 (41%) cases for a total of 2050 GAs, and 180 (46%) KRAS WT cases for a total of 285 GAs. DDR pathway alterations were common in KRAS WT PDAC compared to KRAS mutated PDAC (p = 0.028). Among the 842 (24.6%) cases with available TMB data, 5 (0.6%), 104 (12.3%) and 733 (87.1%) pts had H, I and L, TMB respectively. Among 88 (22.6%) KRAS WT cases with available TMB data, 2 (2.3%), 12 (13.6%) and 74 (84.1%) pts had H, I and L, TMB, respectively. MSI status was available in 2314 (67.5%) cases, 13 (0.6%) were MSI-high (MSI-H); among the KRAS WT cases, 222 (57%) had MSI status available, 3 (1.3%) were MSI-H. Conclusions: MSI-H status and high TMB are rare in PDAC, regardless of KRAS mutation status. GAs in the DDR pathway are relatively common in PDAC and may serve as predictive biomarkers for platinum chemotherapeutic agents and/or PARP inhibitors. Prospective validation of such predictive gene signatures will improve therapeutic efficacy and minimize toxicities.
34
Spaargaren, M., G. A. Martin, F. McCormick, M. J. Fernandez-Sarabia, and J. R. Bischoff. "The Ras-related protein R-ras interacts directly with Raf-1 in a GTP-dependent manner." Biochemical Journal 300, no. 2 (June 1, 1994): 303–7. http://dx.doi.org/10.1042/bj3000303.
Full textAbstract:
R-ras is a member of the ras family of small GTPases that associates with the apoptosis-suppressing proto-oncogene product Bcl-2. Using the yeast two-hybrid system we provide evidence for an interaction between R-ras and the Raf-1 kinase. This interaction requires only the N-terminal regulatory domain (amino acids 1-256) of Raf-1, and is observed with both the wild type and a constitutively active R-ras mutant, but not with a deletion mutant that lacks the potential effector domain or a mutant of R-ras impaired for GTP binding. Moreover, using an in vitro binding assay we show a direct GTP-dependent interaction of purified R-ras with a purified Raf-1 fragment corresponding to the proposed 81-amino-acid H-Ras-binding domain of Raf-1 (amino acids 51-131). Taken together, these data indicate that R-ras may exert its biological effect by means of modulating the activity of the Raf-1 kinase as its direct downstream effector.
35
Nicolazzo, Chiara, Francesca Belardinilli, Annarita Vestri, Valentina Magri, Gianluigi De Renzi, Michela De Meo, Salvatore Caponnetto, et al. "RAS Mutation Conversion in Bevacizumab-Treated Metastatic Colorectal Cancer Patients: A Liquid Biopsy Based Study." Cancers 14, no. 3 (February 4, 2022): 802. http://dx.doi.org/10.3390/cancers14030802.
Full textAbstract:
Liquid biopsies have shown that, in RAS mutant colorectal cancer, the conversion to RAS wild-type * status during the course of the disease is a frequent event, supporting the concept that the evolutionary landscape of colorectal cancer can lead to an unexpected negative selection of RAS mutant clones. The aim of the present study was to clarify whether the negative selection of RAS mutation in plasma might be drug-dependent. For this purpose, we used liquid biopsy to compare the rate of conversion from RAS mutant to RAS wild-type * in two groups of originally RAS mutant mCRC patients: the first treated with chemotherapy alone, while the second was treated with chemotherapy combined with bevacizumab. Serial liquid biopsies were performed at 3 months (T1), 6 months (T2), 9 months (T3), and 12 months (T4) after starting first line treatments. We found that the only independent variable significantly associated to RAS status conversion was the use of bevacizumab. RAS conversion was not found associated to tumor burden reduction, although bevacizumab-treated patients who converted to RAS wild-type * had a significantly longer PFS compared to patients who remained RAS mutant. The appearance of a “RAS wild-type * window”, mainly in bevacizumab-treated patients, might present them as candidates for second line treatment with anti-EGFR, which was otherwise precluded.
36
Mattingly, Raymond R. "Activated Ras as a Therapeutic Target: Constraints on Directly Targeting Ras Isoforms and Wild-Type versus Mutated Proteins." ISRN Oncology 2013 (October 31, 2013): 1–14. http://dx.doi.org/10.1155/2013/536529.
Full textAbstract:
The ability to selectively and directly target activated Ras would provide immense utility for treatment of the numerous cancers that are driven by oncogenic Ras mutations. Patients with disorders driven by overactivated wild-type Ras proteins, such as type 1 neurofibromatosis, might also benefit from progress made in that context. Activated Ras is an extremely challenging direct drug target due to the inherent difficulties in disrupting the protein:protein interactions that underlie its activation and function. Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. Likely reasons for this disappointing outcome include the significant and underappreciated differences in the isoforms of Ras. It is still plausible that inhibition of farnesyl transferase will prove effective for disease that is driven by activated H-Ras. The principal current focus of drugs entering clinic trial is inhibition of pathways downstream of activated Ras, for example, trametinib, a first-in-class MEK inhibitor. The complexity of signaling that is driven by activated Ras indicates that effective inhibition of oncogenic transduction through this approach will be difficult, with resistance being likely to emerge through switch to parallel pathways. Durable disease responses will probably require combinatorial block of several downstream targets.
37
Wang, Chongkai, Ching Ouyang, Jaideep Singh Sandhu, Michael Kahn, and Marwan Fakih. "Wild-type APC and prognosis in metastatic colorectal cancer." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 223. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.223.
Full textAbstract:
223 Background: Somatic mutations at adenomatous polyposis coli ( APC) gene, found in ~75% of colorectal cancers (CRC), are under-represented in microsatellite instable (MSI-H) tumors. While several studies have suggested worse outcomes for CRC patients (pts) with wild-type APC ( APC-WT), the prognostic implication of this genomic alteration in metastatic CRC (mCRC) is not well defined. Methods: APC prognostic value was evaluated in 331 stage IV microsatellite stable (MSS) CRC pts treated in our institution. Next-generation genomic analysis (FoundationOne) was used to characterize the molecular characteristics of APC-WT and mutant APC ( APC-MT) pts. Findings were validated on a public database of stage IV colon cancer from MSKCC. Results: APC-WT was present in 26% of mCRC patients. In comparison to APC-MT population (n = 244), APC-WT pts (n = 87) tended to be younger (median age: 49 vs. 58 years), right-sided (44% vs. 24%), BRAF-V600E mutated (25% vs. 5%), p53 WT (38% vs. 21%) and RAS WT (66% vs. 53%). APC-WT tumors were associated with other Wnt activating alterations ( CTNNB1, FBXW7, RNF43, ARID1A and SOX9). Among those, RNF43 and CTNNB1 were more significantly represented in the APC-WT vs APC-MT population (12% vs 1% and 11% vs 3%, respectively). APC-WT pts had a worse overall survival (OS) than APC-MT pts (30 vs 48 months, HR = 1.809, 95% CI 1.260-2.596, p < 0.0001). Using a multivariate model correcting for primary tumor location, RAS and BRAF status, APC-WT was predictive of poor survival (HR = 1.7, p = 0.001) in our data set. The prognostic implication of APC-WT on OS were confirmed further in a similar multivariate model of 433 stage IV pts from MSKCC public database (HR = 1.6, P = 0.01). Conclusions: APC-WT is associated with poor OS in MSS mCRC regardless of RAS, BRAF status. Compared with APC-MT mCRC tumors, APC-WT tumors were associated with other activating alterations of Wnt pathway, including RNF43 and CTNBB1.
38
Yoshino, Takayuki, Radka Obermannova, Gyorgy Bodoky, Jana Prausová, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, Pilar Garcia Alfonso, et al. "Are BRAF mutated metastatic colorectal cancer (mCRC) tumors more responsive to VEGFR-2 blockage? Analysis of patient outcomes by RAS/RAF mutation status in the RAISE study—A global, randomized, double-blind, phase III study." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 622. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.622.
Full textAbstract:
622 Background: The RAISE trial (NCT01183780) demonstrated that ramucirumab (RAM) plus leucovorin, fluorouracil, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo (PBO) plus FOLFIRI as second-line mCRC treatment. RAS/RAF mutations are associated with resistance to anti-EGFR therapies and poor prognosis, particularly BRAF mutations. The extensive RAISE biomarker program assessed the association of multiple candidate markers with efficacy outcomes. Here we present the results for RAS/ RAF mutations. Methods: Plasma and tumor tissue collection were mandatory. KRAS mutation status was determined locally before randomization. Further RAS and RAF mutations were assessed centrally by multiplex qPCR using the Modaplex system (Qiagen) only in samples that were initially reported as KRAS wild type. Thus, patients were classified into one of the 3 categories in the table. OS and PFS by RAS and RAF subgroups were evaluated by Kaplan-Meier and Cox proportional hazards analyses. Results: As with previously reported KRAS analyses, the favorable RAM treatment effect was similar between patients with expanded RAS mutations compared with patients with RAS/ RAF wild-type tumors. However, in the 41 patients with BRAF mutated tumors, the RAM benefit was even more notable for both OS (hazard ratio [HR] 0.54; 95% CI 0.25–1.13) and PFS (HR 0.55; 95% CI 0.28–1.08). Conclusions: RAISE demonstrated that the addition of RAM to FOLFIRI improved patient outcomes regardless of RAS mutation status. The noteworthy signal for patients with BRAF mutant tumors is encouraging due to their poor prognosis but requires further validation in other clinical trials. Clinical trial information: NCT01183780. [Table: see text]
39
Raimondi, Cristina, Chiara Nicolazzo, Francesca Belardinilli, Flavia Loreni, Angela Gradilone, Yasaman Mahdavian, Alain Gelibter, Giuseppe Giannini, Enrico Cortesi, and Paola Gazzaniga. "Transient Disappearance of RAS Mutant Clones in Plasma: A Counterintuitive Clinical Use of EGFR Inhibitors in RAS Mutant Metastatic Colorectal Cancer." Cancers 11, no. 1 (January 4, 2019): 42. http://dx.doi.org/10.3390/cancers11010042.
Full textAbstract:
Genomic studies performed through liquid biopsies widely elucidated the evolutionary trajectory of RAS mutant clones under the selective pressure of EGFR inhibitors in patients with wild type RAS primary colorectal tumors. Similarly, the disappearance of RAS mutant clones in plasma has been more recently reported in some patients with primary RAS mutant cancers, supporting for the first time an unexpected negative selection of RAS mutations during the clonal evolution of mCRC. To date, the extent of conversion to RAS wild type disease at the time of progression has not been clarified yet. As a proof of concept, we prospectively enrolled mCRC patients progressing under anti-VEGF based treatments. Idylla™ system was used to screen RAS mutations in plasma and the wild type status of RAS was further confirmed through IT-PGM (Ion Torrent Personal Genome Machine) sequencing. RAS was found mutant in 55% of cases, retaining the same plasma mutation as in the primary tumor at diagnosis, while it was found wild-type in 45%. Four patients testing negative for RAS mutations in plasma at the time of progression of disease (PD) were considered eligible for treatment with EGFR inhibitors and treated accordingly, achieving a clinical benefit. We here propose a hypothetical algorithm that accounts for the transient disappearance of RAS mutant clones over time, which might extend the continuum of care of mutant RAS colorectal cancer patients through the delivery of a further line of therapy.
40
Bottorff, D., S. Stang, S. Agellon, and J. C. Stone. "RAS signalling is abnormal in a c-raf1 MEK1 double mutant." Molecular and Cellular Biology 15, no. 9 (September 1995): 5113–22. http://dx.doi.org/10.1128/mcb.15.9.5113.
Full textAbstract:
A mutant rat cell clone that suppresses the transformation defects of RAS effector loop substitutions is heterozygous for mutations in c-raf1 and MEK1. The mutant cells can be transformed by many otherwise defective RAS effector mutants, including RAS genes with the effector regions of distantly related GTPases, even though the encoded RAS proteins do not interact with either the mutant or wild-type RAF in Saccharomyces cerevisiae. While the significance of the c-raf1 mutation is unclear, the MEK1 mutation increases MEK1 activity and leads to activation of mitogen-activated protein kinase. The mutant MEK1 is coupled to the epidermal growth factor pathway but exhibits decreased physical interaction with RAF. When overexpressed, the MEK1 mutation is transforming and causes hyperphosphorylation of RAF. Signalling from RAS to MEK1 may be mediated by something other than RAF alone, but signalling through MEK1 is probably sufficient for RAS transformation.
41
Valladares-Ayerbes, Manuel, Pilar Garcia-Alfonso, Jorge Muñoz Luengo, Paola Patricia Pimentel Caceres, Oscar Alfredo Castillo Trujillo, Rosario Vidal-Tocino, Marta Llanos, et al. "Evolution of RAS Mutations in Cell-Free DNA of Patients with Tissue RAS Wild-Type Metastatic Colorectal Cancer Receiving First-Line Treatment: The PERSEIDA Study." Cancers 14, no. 24 (December 9, 2022): 6075. http://dx.doi.org/10.3390/cancers14246075.
Full textAbstract:
The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS (KRAS/NRAS) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment—panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations (n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients (n = 9; panitumumab subpopulation) presented emergent mutations (RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.
42
Duan, Yifan, Xiaoyu Yin, Xiaorong Lai, Chao Liu, Wenjing Nie, Dongfeng Li, Zijun Xie, Zijun Li, and Fan Meng. "Upregulation of DAB2IP Inhibits Ras Activity and Tumorigenesis in Human Pancreatic Cancer Cells." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303381989549. http://dx.doi.org/10.1177/1533033819895494.
Full textAbstract:
KRAS mutation-induced Ras activation plays an important role in the pathogenesis of pancreatic cancer, but the role of wild-type Ras and Ras GTPase-activating proteins remains unclear. The present study was designed to determine the expression spectra of Ras GTPase-activating proteins genes in pancreatic cancer cells, and the role of DAB2IP, a Ras GTPase-activating proteins gene, in the development and progression of pancreatic cancer. Following the analyses of the expression profiles of 16 Ras GTPase-activating proteins in 6 pancreatic cancer cell lines including Bxpc-3 (with wild-type KRAS), Capan-2, Sw1990, Aspc-1, CFPAC-1, and Panc-1 (with mutant KRAS) and 1 normal human pancreatic ductal epithelial cell line, H6C7, the expression of DAB2IP messenger RNA was further analyzed by quantitative real-time polymerase chain reaction. The role of DAB2IP in pancreatic cancer was further investigated in vitro and in vivo by upregulating DAB2IP in Bxpc-3 cells through transfection of DAB2IP into Bxpc-3 cells with recombinant lentivirus. The DAB2IP expression in pancreatic cancer cells and tissues with wild-type KRAS was significantly lower than that in cells and tissues with mutant KRAS ( P < .05). In Bxpc-3 cells with wild-type KRAS, overexpression of DAB2IP decreased the expression of P-AKT and P-ERK and the Ras activity; increased the expression of P-JNK and caspase 3; inhibited cell proliferation, invasiveness, and migration; and increased the cell sensitivity to cetuximab. Overexpression of DAB2IP inhibited tumor progression in a mouse model. In conclusion, DAB2IP downregulates Ras activity in wild-type pancreatic cancer cells. Overexpression of DAB2IP decreases the Ras activity, inhibits cell proliferation, and increases sensitivity to cetuximab in wild-type pancreatic cancer cells. In conclusion, DAB2IP may serve as a potential molecular therapeutic target for the treatment of pancreatic cancer.
43
Hill, Kristen S., Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, and Minjung Kim. "Abstract PR13: PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas." Cancer Research 80, no. 19_Supplement (October 1, 2020): PR13. http://dx.doi.org/10.1158/1538-7445.mel2019-pr13.
Full textAbstract:
Abstract Melanoma is one of the most highly mutated cancer types, harboring numerous alterations with unknown significance. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells. PTPN11 played oncogenic roles in melanoma by driving anchorage-independent colony formation and tumor growth. In Pten and Cdkn2a null mice, tet-inducible and melanocyte-specific PTPN11E76K expression significantly enhanced melanoma tumorigenesis. Melanoma cells derived from this mouse model showed doxycycline-dependent tumor growth in nude mice. Silencing PTPN11E76K expression by doxycycline withdrawal caused regression of established tumors by induction of apoptosis and senescence and suppression of proliferation. Moreover, the PTPN11 inhibitor (SHP099) also caused regression of NRASQ61K-mutant melanoma. Using a quantitative tyrosine phospho-proteomics approach, we identified GSK3α/β as one of the key substrates that were differentially tyrosine-phosphorylated in these experiments modulating PTPN11. This study demonstrates that PTPN11 plays oncogenic roles in melanoma and regulates RAS and GSK3α/β signaling pathways. This study also identifies PTPN11 as a novel and actionable therapeutic target for BRAF wild-type melanoma. This abstract is also being presented as Poster A14. Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, John M. Koomen, Jane L. Messina, Jamie K. Teer, Youngchul Kim, Jie Wu, Charles E. Chalfant, Minjung Kim. PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR13.
44
Diaz, B., D. Barnard, A. Filson, S. MacDonald, A. King, and M. Marshall. "Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling." Molecular and Cellular Biology 17, no. 8 (August 1997): 4509–16. http://dx.doi.org/10.1128/mcb.17.8.4509.
Full textAbstract:
Activation of the Raf serine/threonine protein kinases is tightly regulated by multiple phosphorylation events. Phosphorylation of either tyrosine 340 or 341 in the catalytic domain of Raf-1 has been previously shown to induce the ability of the protein kinase to phosphorylate MEK. By using a combination of mitogenic and enzymatic assays, we found that phosphorylation of the adjacent residue, serine 338, and, to a lesser extent, serine 339 is essential for the biological and enzymatic activities of Raf-1. Replacement of S338 with alanine blocked the ability of prenylated Raf-CX to transform Rat-1 fibroblasts. Similarly, the loss of S338-S339 in Raf-1 prevented protein kinase activation in COS-7 cells by either oncogenic Ras[V12] or v-Src. Consistent with phosphorylation of S338-S339, acidic amino acid substitutions of these residues partially restored transforming activity to Raf-CX, as well as kinase activation of Raf-1 by Ras[V12] or v-Src. Two-dimensional phosphopeptide mapping of wild-type Raf-CX and Raf-CX[A338A339] confirmed the presence of a phosphoserine-containing peptide with the predicted mobility in the wild-type protein which was absent from the mutant. This peptide could be quantitatively precipitated by an antipeptide antibody specific for the 18-residue tryptic peptide containing S338-S339 and was demonstrated to contain only phosphoserine. Phosphorylation of this peptide in Raf-1 was significantly increased by coexpression with Ras[V12]. These data demonstrate that Raf-1 residues 338 to 341 constitute a unique phosphoregulatory site in which the phosphorylation of serine and tyrosine residues contributes to the regulation of Raf by Ras, Src, and Ras-independent membrane localization.
45
Romano, David, Helene Maccario, Carolanne Doherty, Niall P. Quinn, Walter Kolch, and David Matallanas. "The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics." Molecular and Cellular Biology 33, no. 9 (March 4, 2013): 1859–68. http://dx.doi.org/10.1128/mcb.01414-12.
Full textAbstract:
K-Ras is frequently mutated in human cancers. Mutant (mt) K-Ras can stimulate both oncogenic transformation and apoptosis through activation of extracellular signal-regulated kinase (ERK) and AKT pathways and the MST2 pathway, respectively. The biological outcome is determined by the balance and cross talk between these pathways. In colorectal cancer (CRC), a K-Ras mutation is negatively correlated with MST2 expression, as mt K-Ras can induce apoptosis by activating the MST2 pathway. However, wild-type (wt) K-Ras can prevent the activation of the MST2 pathway upon growth factor stimulation and enable transformation by mt K-Ras in CRC cells that express MST2. Here we have investigated the mechanism by which wt and mt K-Ras differentially regulate the MST2 pathway and MST2-dependent apoptosis. The ability of K-Ras to activate MST2 and MST2-dependent apoptosis is determined by the differential activation kinetics of mt K-Ras and wt K-Ras. Chronic activation of K-Ras by mutation or overexpression of Ras exchange factors results in the activation of MST2 and LATS1, increased MST2-LATS1 complex formation, and apoptosis. In contrast, transient K-Ras activation upon epidermal growth factor (EGF) stimulation prevents the formation of the MST2-LATS1 complex in an AKT-dependent manner. Our data suggest that the close relationship between Ras prosurvival and proapoptotic signaling is coordinated via the differential regulation of the MST2-LATS1 interaction by transient and chronic stimuli.
46
Garcia, Josefina, Jean de Gunzburg, Alain Eychène, Sylvie Gisselbrecht, and Françoise Porteu. "Thrombopoietin-Mediated Sustained Activation of Extracellular Signal-Regulated Kinase in UT7-Mpl Cells Requires Both Ras–Raf-1- and Rap1–B-Raf-Dependent Pathways." Molecular and Cellular Biology 21, no. 8 (April 15, 2001): 2659–70. http://dx.doi.org/10.1128/mcb.21.8.2659-2670.2001.
Full textAbstract:
ABSTRACT Thrombopoietin (TPO) regulates growth and differentiation of megakaryocytes. We previously showed that extracellular signal-regulated kinases (ERKs) are required for TPO-mediated full megakaryocytic maturation in both normal progenitors and a megakaryoblastic cell line (UT7) expressing the TPO receptor (Mpl). In these cells, intensity and duration of TPO-induced ERK signal are controlled by several regions of the cytoplasmic domain of Mpl. In this study, we explored the signaling pathways involved in this control. We show that the small GTPases Ras and Rap1 contribute together to TPO-induced ERK activation in UT7-Mpl cells and that they do so by activating different Raf kinases as downstream effectors: a Ras–Raf-1 pathway is required to initiate ERK activation while Rap1 sustains this signal through B-Raf. Indeed, (i) in cells expressing wild-type or mutant Mpl, TPO-induced Ras and Rap1 activation correlates with early and sustained phases of ERK signal, respectively; (ii) interfering mutants of Ras and Rap1 both inhibit ERK kinase activity and ERK-dependent Elk1 transcriptional activation in response to TPO; (iii) the kinetics of activation of Raf-1 and B-Raf by TPO follow those of Ras and Rap1, respectively; (iv) RasV12-mediated Elk1 activation was modulated by the wild type or interfering mutants of Raf-1 but not those of B-Raf; (v) Elk1 activation mediated by a constitutively active mutant of Rap1 (Rap1V12) is potentiated by B-Raf and inhibited by an interfering mutant of this kinase. UT7-Mpl cells represent the second cellular model in which Ras and Rap1 act in concert to modulate the duration of ERK signal in response to a growth factor and thereby the differentiation program. This is also, to our knowledge, the first evidence suggesting that Rap1 may play an active role in megakaryocytic maturation.
47
Van Cutsem, Eric, Heinz-Josef Lenz, Claus-Henning Köhne, Volker Heinemann, Sabine Tejpar, Ivan Melezínek, Frank Beier, et al. "Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer." Journal of Clinical Oncology 33, no. 7 (March 1, 2015): 692–700. http://dx.doi.org/10.1200/jco.2014.59.4812.
Full textAbstract:
Purpose The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing. Patients and Methods Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations. Results Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations. Conclusion In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti–epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
48
Khare, S., S. Cerda, R. Wali, F. C. Von Lintig, M. Tretiakova, D. Stoiber, G. Cohen, et al. "Ursodeoxycholic acid inhibits ras mutations, wild type ras activation and cyclooxygenase-2 expression in colon cancer." Gastroenterology 124, no. 4 (April 2003): A605. http://dx.doi.org/10.1016/s0016-5085(03)83066-4.
Full text
49
Matallanas, David, David Romano, Fahd Al-Mulla, Eric O'Neill, Waleed Al-Ali, Piero Crespo, Brendan Doyle, et al. "Mutant K-Ras Activation of the Proapoptotic MST2 Pathway Is Antagonized by Wild-Type K-Ras." Molecular Cell 44, no. 6 (December 2011): 893–906. http://dx.doi.org/10.1016/j.molcel.2011.10.016.
Full text
50
Tavares, N., A. Costa, D. Almeida, S. Meireles, C. Fernandes, C. Rey, C. Sarmento, and M. Damasceno. "The prognostic impact of sidedness in RAS wild-type colorectal cancer." Annals of Oncology 29 (June 2018): v75. http://dx.doi.org/10.1093/annonc/mdy151.266.
Full text