Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Review Article

The Function of RAS Mutation in Cancer and Advances in its Drug Research

Author(s): Shijie Chen, Fengyang Li, Dan Xu, Kai Hou, Weirong Fang* and Yunman Li*

Volume 25, Issue 10, 2019

Page: [1105 - 1114] Pages: 10

DOI: 10.2174/1381612825666190506122228

Price: $65

Abstract

RAS (H-ras, K-ras, and N-ras), as the second largest mutated gene driver in various human cancers, has long been a vital research target for cancer. Its function is to transform the extracellular environment into a cascade of intracellular signal transduction. RAS mutant protein regulates tumor cell proliferation, apoptosis, metabolism and angiogenesis through downstream MAPK, PI3K and other signaling pathways. In KRAS or other RAS-driven cancers, current treatments include direct inhibitors and upstream/downstream signaling pathway inhibitors. However, the research on these inhibitors has been largely restricted due to their escape inhibition and off-target toxicity. In this paper, we started with the role of normal and mutant RAS genes in cancer, elucidated the relevant RAS regulating pathways, and highlighted the important research advancements in RAS inhibitor research. We concluded that for the crosstalk between RAS pathways, the effect of single regulation may be limited, and the multi-target drug combined compensation mechanism is becoming a research hotspot.

Keywords: RAS mutation, KRAS, cancer, inhibitor, targeted drug, signal pathway.

« Previous Next »
[1]
GALEY P. Cancer to kill 10 mn in 2018 despite better prevention. 2018.https://www.yahoo.com/news/cancer-kill-10-mn-2018-despite-better-prevention-140043457.html
[2]
Simanshu DK, Nissley DV, McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell 2017; 170(1): 17-33.
[http://dx.doi.org/10.1016/j.cell.2017.06.009] [PMID: 28666118]
[3]
Cox AD, Der CJ. Ras history: The saga continues. Small GTPases 2010; 1(1): 2-27.
[http://dx.doi.org/10.4161/sgtp.1.1.12178] [PMID: 21686117]
[4]
Martincorena I, Campbell PJ. Somatic mutation in cancer and normal cells. Science 2015; 349(6255): 1483-9.
[http://dx.doi.org/10.1126/science.aab4082] [PMID: 26404825]
[5]
Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017; 23(6): 703-13.
[http://dx.doi.org/10.1038/nm.4333] [PMID: 28481359]
[6]
Haigis KM. KRAS Alleles: The Devil Is in the Detail. Trends Cancer 2017; 3(10): 686-97.
[http://dx.doi.org/10.1016/j.trecan.2017.08.006] [PMID: 28958387]
[7]
Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov 2014; 13(11): 828-51.
[http://dx.doi.org/10.1038/nrd4389] [PMID: 25323927]
[8]
To MD, Rosario RD, Westcott PM, Banta KL, Balmain A. Interactions between wild-type and mutant Ras genes in lung and skin carcinogenesis. Oncogene 2013; 32(34): 4028-33.
[http://dx.doi.org/10.1038/onc.2012.404] [PMID: 22945650]
[9]
Yu CC, Qiu W, Juang CS, Mansukhani MM, Halmos B, Su GH. Mutant allele specific imbalance in oncogenes with copy number alterations: Occurrence, mechanisms, and potential clinical implications. Cancer Lett 2017; 384: 86-93.
[http://dx.doi.org/10.1016/j.canlet.2016.10.013] [PMID: 27725226]
[10]
Burgess MR, Hwang E, Mroue R, et al. KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer. Cell 2017; 168(5): 817-829.e15.
[http://dx.doi.org/10.1016/j.cell.2017.01.020] [PMID: 28215705]
[11]
Doherty GJ, Kerr EM, Martins CP. KRAS Allelic Imbalance: Strengths and Weaknesses in Numbers. Trends Mol Med 2017; 23(5): 377-8.
[http://dx.doi.org/10.1016/j.molmed.2017.03.005] [PMID: 28372922]
[12]
Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. Understanding Ras: ‘it ain’t over ’til it’s over’. Trends Cell Biol 2000; 10(4): 147-54.
[http://dx.doi.org/10.1016/S0962-8924(00)01740-2] [PMID: 10740269]
[13]
Yuan TL, Amzallag A, Bagni R, et al. Differential Effector Engagement by Oncogenic KRAS. Cell Rep 2018; 22(7): 1889-902.
[http://dx.doi.org/10.1016/j.celrep.2018.01.051] [PMID: 29444439]
[14]
Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 1993; 363(6424): 45-51.
[http://dx.doi.org/10.1038/363045a0] [PMID: 8479536]
[15]
Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003; 3(1): 11-22.
[http://dx.doi.org/10.1038/nrc969] [PMID: 12509763]
[16]
Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 2011; 11(11): 761-74.
[http://dx.doi.org/10.1038/nrc3106] [PMID: 21993244]
[17]
Leevers SJ, Paterson HF, Marshall CJ. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 1994; 369(6479): 411-4.
[http://dx.doi.org/10.1038/369411a0] [PMID: 8196769]
[18]
Vojtek AB, Hollenberg SM, Cooper JA. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 1993; 74(1): 205-14.
[http://dx.doi.org/10.1016/0092-8674(93)90307-C] [PMID: 8334704]
[19]
Roskoski R Jr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 2012; 66(2): 105-43.
[http://dx.doi.org/10.1016/j.phrs.2012.04.005] [PMID: 22569528]
[20]
Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010; 28(6): 1075-83.
[http://dx.doi.org/10.1200/JCO.2009.25.3641] [PMID: 20085938]
[21]
Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005; 16(4): 525-37.
[http://dx.doi.org/10.1093/annonc/mdi113] [PMID: 15728109]
[22]
Burridge K, Wennerberg K. Rho and Rac take center stage. Cell 2004; 116(2): 167-79.
[http://dx.doi.org/10.1016/S0092-8674(04)00003-0] [PMID: 14744429]
[23]
Neel NF, Martin TD, Stratford JK, Zand TP, Reiner DJ, Der CJ. The RalGEF-Ral Effector Signaling Network: The Road Less Traveled for Anti-Ras Drug Discovery. Genes Cancer 2011; 2(3): 275-87.
[http://dx.doi.org/10.1177/1947601911407329] [PMID: 21779498]
[24]
Kelley GG, Reks SE, Ondrako JM, Smrcka AV. Phospholipase C(epsilon): a novel Ras effector. EMBO J 2001; 20(4): 743-54.
[http://dx.doi.org/10.1093/emboj/20.4.743] [PMID: 11179219]
[25]
Symonds JM, Ohm AM, Carter CJ, et al. Protein kinase C δ is a downstream effector of oncogenic K-ras in lung tumors. Cancer Res 2011; 71(6): 2087-97.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1511] [PMID: 21335545]
[26]
Zhang RY, Du WQ, Zhang YC, Zheng JN, Pei DS. PLCε signaling in cancer. J Cancer Res Clin Oncol 2016; 142(4): 715-22.
[http://dx.doi.org/10.1007/s00432-015-1999-x] [PMID: 26109147]
[27]
Scheffzek K, Ahmadian MR, Kabsch W, et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997; 277(5324): 333-8.
[http://dx.doi.org/10.1126/science.277.5324.333] [PMID: 9219684]
[28]
Feramisco JR, Gross M, Kamata T, Rosenberg M, Sweet RW. Microinjection of the oncogene form of the human H-ras (T-24) protein results in rapid proliferation of quiescent cells. Cell 1984; 38(1): 109-17.
[http://dx.doi.org/10.1016/0092-8674(84)90531-2] [PMID: 6380758]
[29]
Daly AC, Vizán P, Hill CS. Smad3 protein levels are modulated by Ras activity and during the cell cycle to dictate transforming growth factor-beta responses. J Biol Chem 2010; 285(9): 6489-97.
[http://dx.doi.org/10.1074/jbc.M109.043877] [PMID: 20037158]
[30]
Kretzschmar M, Doody J, Timokhina I, Massagué J. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev 1999; 13(7): 804-16.
[http://dx.doi.org/10.1101/gad.13.7.804] [PMID: 10197981]
[31]
Drosten M, Dhawahir A, Sum EY, et al. Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J 2010; 29(6): 1091-104.
[http://dx.doi.org/10.1038/emboj.2010.7] [PMID: 20150892]
[32]
Drosten M, Sum EY, Lechuga CG, et al. Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway. Proc Natl Acad Sci USA 2014; 111(42): 15155-60.
[http://dx.doi.org/10.1073/pnas.1417549111] [PMID: 25288756]
[33]
Stout MC, Asiimwe E, Birkenstamm JR, Kim SY, Campbell PM. Analyzing Ras-associated cell proliferation signaling. Methods Mol Biol 2014; 1170: 393-409.
[http://dx.doi.org/10.1007/978-1-4939-0888-2_21] [PMID: 24906326]
[34]
Leone G, DeGregori J, Sears R, Jakoi L, Nevins JR. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 1997; 387(6631): 422-6.
[http://dx.doi.org/10.1038/387422a0] [PMID: 9163430]
[35]
Cao L, Peng B, Yao L, et al. The ancient function of RB-E2F pathway: insights from its evolutionary history. Biol Direct 2010; 5: 55.
[http://dx.doi.org/10.1186/1745-6150-5-55] [PMID: 20849664]
[36]
Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev 1998; 8(1): 49-54.
[http://dx.doi.org/10.1016/S0959-437X(98)80061-0] [PMID: 9529605]
[37]
Joneson T, Bar-Sagi D. Suppression of Ras-induced apoptosis by the Rac GTPase. Mol Cell Biol 1999; 19(9): 5892-901.
[http://dx.doi.org/10.1128/MCB.19.9.5892] [PMID: 10454536]
[38]
Sahu RP, Batra S, Kandala PK, Brown TL, Srivastava SK. The role of K-ras gene mutation in TRAIL-induced apoptosis in pancreatic and lung cancer cell lines. Cancer Chemother Pharmacol 2011; 67(2): 481-7.
[http://dx.doi.org/10.1007/s00280-010-1463-1] [PMID: 20848283]
[39]
Carter BZ, Qiu YH, Zhang N, et al. Expression of ARC (apoptosis repressor with caspase recruitment domain), an antiapoptotic protein, is strongly prognostic in AML. Blood 2011; 117(3): 780-7.
[http://dx.doi.org/10.1182/blood-2010-04-280503] [PMID: 21041716]
[40]
Chen H, Wang J, Hu B, et al. MiR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2. Mol Cell Biochem 2015; 406(1-2): 21-30.
[http://dx.doi.org/10.1007/s11010-015-2420-4] [PMID: 25910896]
[41]
Medina-Ramirez CM, Goswami S, Smirnova T, et al. Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance. Cancer Res 2011; 71(24): 7705-15.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-2192] [PMID: 22037876]
[42]
Speidel D. Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol 2010; 20(1): 14-24.
[http://dx.doi.org/10.1016/j.tcb.2009.10.002] [PMID: 19879762]
[43]
Cox AD, Der CJ. The dark side of Ras: regulation of apoptosis. Oncogene 2003; 22(56): 8999-9006.
[http://dx.doi.org/10.1038/sj.onc.1207111] [PMID: 14663478]
[44]
Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11(2): 85-95.
[http://dx.doi.org/10.1038/nrc2981] [PMID: 21258394]
[45]
Gaglio D, Metallo CM, Gameiro PA, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol 2011; 7: 523.
[http://dx.doi.org/10.1038/msb.2011.56] [PMID: 21847114]
[46]
Mason JA, Davison-Versagli CA, Leliaert AK, et al. Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells. Cell Death Differ 2016; 23(8): 1271-82.
[http://dx.doi.org/10.1038/cdd.2016.15] [PMID: 26915296]
[47]
Khatri S, Yepiskoposyan H, Gallo CA, Tandon P, Plas DR. FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J Biol Chem 2010; 285(21): 15960-5.
[http://dx.doi.org/10.1074/jbc.M110.121871] [PMID: 20371605]
[48]
Shi L, Pan H, Liu Z, Xie J, Han W. Roles of PFKFB3 in cancer. Signal Transduct Target Ther 2017; 2: 17044.
[http://dx.doi.org/10.1038/sigtrans.2017.44] [PMID: 29263928]
[49]
Guo JY, Chen HY, Mathew R, et al. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev 2011; 25(5): 460-70.
[http://dx.doi.org/10.1101/gad.2016311] [PMID: 21317241]
[50]
Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med 2011; 17(7): 347-62.
[http://dx.doi.org/10.1016/j.molmed.2011.01.015] [PMID: 21481637]
[51]
Zhao Y, Xiao A, Dipierro CG, et al. H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway. Glia 2008; 56(8): 917-24.
[http://dx.doi.org/10.1002/glia.20667] [PMID: 18383343]
[52]
Caetano MS, Zhang H, Cumpian AM, et al. IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer. Cancer Res 2016; 76(11): 3189-99.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-2840] [PMID: 27197187]
[53]
Weijzen S, Velders MP, Kast WM. Modulation of the immune response and tumor growth by activated Ras. Leukemia 1999; 13(4): 502-13.
[http://dx.doi.org/10.1038/sj.leu.2401367] [PMID: 10214854]
[54]
Mason JA, Schafer ZT. Ras-ling with new therapeutic targets for metastasis. Small GTPases 2017; 10(4): 249-53.
[http://dx.doi.org/10.1080/21541248.2017.1310650] [PMID: 28471257]
[55]
Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov 2016; 15(11): 771-85.
[http://dx.doi.org/10.1038/nrd.2016.139] [PMID: 27469033]
[56]
Maurer T, Garrenton LS, Oh A, et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc Natl Acad Sci USA 2012; 109(14): 5299-304.
[http://dx.doi.org/10.1073/pnas.1116510109] [PMID: 22431598]
[57]
Wang W, Fang G, Rudolph J. Ras inhibition via direct Ras binding--is there a path forward? Bioorg Med Chem Lett 2012; 22(18): 5766-76.
[http://dx.doi.org/10.1016/j.bmcl.2012.07.082] [PMID: 22902659]
[58]
Wang Y, Kaiser CE, Frett B, Li HY. Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators. J Med Chem 2013; 56(13): 5219-30.
[http://dx.doi.org/10.1021/jm3017706] [PMID: 23566315]
[59]
Winter-Vann AM, Casey PJ. Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 2005; 5(5): 405-12.
[http://dx.doi.org/10.1038/nrc1612] [PMID: 15864282]
[60]
Jin Y, Li L, Yang Z, Liu M, Guo H, Shen W. The discovery of a novel compound with potent antitumor activity: virtual screening, synthesis, biological evaluation and preliminary mechanism study. Oncotarget 2017; 8(15): 24635-43.
[http://dx.doi.org/10.18632/oncotarget.15601] [PMID: 28445950]
[61]
Schmick M, Vartak N, Papke B, et al. KRas localizes to the plasma membrane by spatial cycles of solubilization, trapping and vesicular transport. Cell 2014; 157(2): 459-71.
[http://dx.doi.org/10.1016/j.cell.2014.02.051] [PMID: 24725411]
[62]
Zimmermann G, Papke B, Ismail S, et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature 2013; 497(7451): 638-42.
[http://dx.doi.org/10.1038/nature12205] [PMID: 23698361]
[63]
Martín-Gago P, Fansa EK, Klein CH, et al. A PDE6δ-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2. Angew Chem Int Ed Engl 2017; 56(9): 2423-8.
[http://dx.doi.org/10.1002/anie.201610957] [PMID: 28106325]
[64]
Papke B, Murarka S, Vogel HA, et al. Identification of pyrazolopyridazinones as PDEδ inhibitors. Nat Commun 2016; 7: 11360.
[http://dx.doi.org/10.1038/ncomms11360] [PMID: 27094677]
[65]
Khan I, Spencer-Smith R, O’Bryan JP. Targeting the alpha4-alpha5 dimerization interface of K-RAS inhibits tumor formation in vivo. Oncogene 2018.
[PMID: 30573767]
[66]
Spencer-Smith R, Koide A, Zhou Y, et al. Inhibition of RAS function through targeting an allosteric regulatory site. Nat Chem Biol 2017; 13(1): 62-8.
[http://dx.doi.org/10.1038/nchembio.2231] [PMID: 27820802]
[67]
Hansen R, Peters U, Babbar A, et al. The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors. Nat Struct Mol Biol 2018; 25(6): 454-62.
[http://dx.doi.org/10.1038/s41594-018-0061-5] [PMID: 29760531]
[68]
Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD. Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol Cancer Res 2015; 13(9): 1325-35.
[http://dx.doi.org/10.1158/1541-7786.MCR-15-0203] [PMID: 26037647]
[69]
Janes MR, Zhang J, Li LS, et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell 2018; 172(3): 578-589.e17.
[http://dx.doi.org/10.1016/j.cell.2018.01.006] [PMID: 29373830]
[70]
Ross SJ, Revenko AS, Hanson LL, et al. Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci Transl Med 2017; 9(394): 9.
[http://dx.doi.org/10.1126/scitranslmed.aal5253] [PMID: 28615361]
[71]
Chen YN, LaMarche MJ, Chan HM, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 2016; 535(7610): 148-52.
[http://dx.doi.org/10.1038/nature18621] [PMID: 27362227]
[72]
Dardaei L, Wang HQ, Singh M, et al. SHP2 inhibition restores sensitivity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors. Nat Med 2018; 24(4): 512-7.
[http://dx.doi.org/10.1038/nm.4497] [PMID: 29505033]
[73]
Pal SK, Figlin RA, Reckamp K. Targeted therapies for non-small cell lung cancer: an evolving landscape. Mol Cancer Ther 2010; 9(7): 1931-44.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0239] [PMID: 20571071]
[74]
Wang S, An T, Wang J, et al. Potential clinical significance of a plasma-based KRAS mutation analysis in patients with advanced non-small cell lung cancer. Clin Cancer Res 2010; 16(4): 1324-30.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-2672] [PMID: 20145159]
[75]
Chen JY, Cheng YN, Han L, et al. Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis. Cancer Biol Med 2015; 12(2): 126-39.
[PMID: 26175928]
[76]
Balak MN, Gong Y, Riely GJ, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006; 12(21): 6494-501.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1570]] [PMID: 17085664] ]
[77]
Yun J, Hong MH, Kim SY, et al. YH25448, an irreversible EGFR-TKI with Potent Intracranial Activity in EGFR mutant non-small-cell lung cancer. Clin Cancer Res 2019; 25(8): 2575-87.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2906]] [PMID: 30670498]
[78]
Jia Y, Yun CH, Park E, et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 2016; 534(7605): 129-32.
[http://dx.doi.org/10.1038/nature17960]] [PMID: 27251290]
[79]
Kannan S, Venkatachalam G, Lim HH, Surana U, Verma C. Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket. Chem Sci (Camb) 2018; 9(23): 5212-22.
[http://dx.doi.org/10.1039/C8SC01262H]] [PMID: 29997876]
[80]
Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64(19): 7099-109.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1443]] [PMID: 15466206] ]
[81]
Takahashi S. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull 2011; 34(12): 1785-8.
[http://dx.doi.org/10.1248/bpb.34.1785]] [PMID: 22130231]
[82]
Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464(7287): 427-30.
[http://dx.doi.org/10.1038/nature08902] ] [PMID: 20179705]
[83]
Yao Z, Gao Y, Su W, et al. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med 2018.
[PMID: 30559419]
[84]
Shao W, Mishina YM, Feng Y, et al. Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF. Cancer Res 2018; 78(6): 1537-48.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-2033] ] [PMID: 29343524]
[85]
Cheng Y, Wang X, Xia X, Zhang W, Tian H. A benzoxazole compound as a novel MEK inhibitor for the treatment of RAS/RAF mutant cancer. Int J Cancer 2019.
[http://dx.doi.org/10.1002/ijc.32119]] [PMID: 30628057] ]
[86]
Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev Clin Oncol 2014; 11(7): 385-400.
[http://dx.doi.org/10.1038/nrclinonc.2014.83] ] [PMID: 24840079]
[87]
Little AS, Balmanno K, Sale MJ, et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal 2011; 4(166): ra17.
[http://dx.doi.org/10.1126/scisignal.2001752]] [PMID: 21447798]
[88]
Holt SV, Logié A, Odedra R, et al. The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. Br J Cancer 2012; 106(5): 858-66.
[http://dx.doi.org/10.1038/bjc.2012.8]] [PMID: 22343622]
[89]
Jaiswal BS, Durinck S, Stawiski EW, et al. ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy. Clin Cancer Res 2018; 24(16): 4044-55.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-3674] ] [PMID: 29760222] ]
[90]
Hayes TK, Neel NF, Hu C, et al. Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell 2016; 29(1): 75-89.
[http://dx.doi.org/10.1016/j.ccell.2015.11.011]] [PMID: 26725216]
[91]
Poulikakos PI, Solit DB. Resistance to MEK inhibitors: should we co-target upstream? Sci Signal 2011; 4(166): pe16.
[http://dx.doi.org/10.1126/scisignal.2001948]] [PMID: 21447797]
[92]
Janku F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients. Cancer Treat Rev 2017; 59: 93-101.
[http://dx.doi.org/10.1016/j.ctrv.2017.07.005] [PMID: 28779636]
[93]
She QB, Chandarlapaty S, Ye Q, et al. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One 2008; 3(8): e3065.
[http://dx.doi.org/10.1371/journal.pone.0003065]] [PMID: 18725974]
[94]
Galoian K, Temple HT, Galoyan A. mTORC1 inhibition and ECM-cell adhesion-independent drug resistance via PI3K-AKT and PI3K-RAS-MAPK feedback loops. Tumour Biol 2012; 33(3): 885-90.
[http://dx.doi.org/10.1007/s13277-011-0315-x]] [PMID: 22246604]
[95]
Will M, Qin AC, Toy W, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov 2014; 4(3): 334-47.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0611]] [PMID: 24436048] ]
[96]
Serra V, Scaltriti M, Prudkin L, et al. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 2011; 30(22): 2547-57.
[http://dx.doi.org/10.1038/onc.2010.626]] [PMID: 21278786]
[97]
Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol 2018; 15(5): 273-91.
[http://dx.doi.org/10.1038/nrclinonc.2018.28]] [PMID: 29508857]
[98]
Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Evers BM. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. J Surg Res 2012; 176(2): 542-8.
[http://dx.doi.org/10.1016/j.jss.2011.10.045]] [PMID: 22261591]
[99]
Peschard P, McCarthy A, Leblanc-Dominguez V, et al. Genetic deletion of RALA and RALB small GTPases reveals redundant functions in development and tumorigenesis. Curr Biol 2012; 22(21): 2063-8.
[http://dx.doi.org/10.1016/j.cub.2012.09.013]] [PMID: 23063435]
[100]
Kissil JL, Walmsley MJ, Hanlon L, et al. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res 2007; 67(17): 8089-94.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-2300] ] [PMID: 17804720] ]
[101]
Anderson GR, Winter PS, Lin KH, et al. A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution. Cell Rep 2017; 20(4): 999-1015.
[http://dx.doi.org/10.1016/j.celrep.2017.07.006]] [PMID: 28746882]
[102]
Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001; 93(14): 1062-74.
[http://dx.doi.org/10.1093/jnci/93.14.1062]] [PMID: 11459867]
[103]
Thompson H. US National Cancer Institute’s new Ras project targets an old foe. Nat Med 2013; 19(8): 949-50.
[http://dx.doi.org/10.1038/nm0813-949]] [PMID: 23921727]
[104]
Morris EJ, Jha S, Restaino CR, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 2013; 3(7): 742-50.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0070]] [PMID: ="pmid"> 23614898]

Rights & Permissions Print Cite
Article Metrics
149
28
2
1
© 2024 Bentham Science Publishers | Privacy Policy