1932

Abstract

Aberrations in rat sarcoma (RAS) viral oncogene are the most prevalent and best-known genetic alterations identified in human cancers. Indeed, RAS drives tumorigenesis as one of the downstream effectors of EGFR activation, regulating cellular switches and functions and triggering intracellular signaling cascades such as the MAPK and PI3K pathways. Of the three RAS isoforms expressed in human cells, all of which were linked to tumorigenesis more than three decades ago, KRAS is the most frequently mutated. In particular, point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. Unfortunately, there are no approved KRAS-targeted agents, despite decades of research and development. Recently, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for renewed drug development efforts, specifically against KRASG12C. These inhibitors, such as AMG 510 and MRTX849, show promise in early-phase studies. Nevertheless, combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors.

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2021-01-27
2024-03-28
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Literature Cited

  1. 1. 
    Chang EH, Gonda MA, Ellis RW et al. 1982. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. PNAS 79:4848–52
    [Google Scholar]
  2. 2. 
    Cooper GM. 1982. Cellular transforming genes. Science 217:801–6
    [Google Scholar]
  3. 3. 
    Malumbres M, Barbacid M. 2003. RAS oncogenes: the first 30 years. Nat. Rev. Cancer 3:459–65
    [Google Scholar]
  4. 4. 
    Harvey JJ. 1964. An unidentified virus which causes the rapid production of tumours in mice. Nature 204:1104–5
    [Google Scholar]
  5. 5. 
    Santos E, Tronick SR, Aaronson SA et al. 1982. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature 298:343–47
    [Google Scholar]
  6. 6. 
    Kirsten WH, Schauf V, McCoy J 1970. Properties of a murine sarcoma virus. Bibl. Haematol. 1970:246–49
    [Google Scholar]
  7. 7. 
    Parada LF, Tabin CJ, Shih C, Weinberg RA 1982. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297:474–78
    [Google Scholar]
  8. 8. 
    Bourne HR, Sanders DA, McCormick F 1991. The GTPase superfamily: conserved structure and molecular mechanism. Nature 349:117–27
    [Google Scholar]
  9. 9. 
    Santos E, Nebreda AR. 1989. Structural and functional properties of ras proteins. FASEB J 3:2151–63
    [Google Scholar]
  10. 10. 
    Riely GJ, Marks J, Pao W 2009. KRAS mutations in non-small cell lung cancer. Proc. Am. Thorac. Soc. 6:201–5
    [Google Scholar]
  11. 11. 
    Eser S, Schnieke A, Schneider G, Saur D 2014. Oncogenic KRAS signalling in pancreatic cancer. Br. J. Cancer 111:817–22
    [Google Scholar]
  12. 12. 
    Fernandez-Medarde A, Santos E. 2011. Ras in cancer and developmental diseases. Genes Cancer 2:344–58
    [Google Scholar]
  13. 13. 
    Downward J. 2003. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3:11–22
    [Google Scholar]
  14. 14. 
    Biankin AV, Waddell N, Kassahn KS et al. 2012. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491:399–405
    [Google Scholar]
  15. 15. 
    Fearon ER, Vogelstein B. 1990. A genetic model for colorectal tumorigenesis. Cell 61:759–67
    [Google Scholar]
  16. 16. 
    Neumann J, Zeindl-Eberhart E, Kirchner T, Jung A 2009. Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol. Res. Pract. 205:858–62
    [Google Scholar]
  17. 17. 
    Karachaliou N, Mayo C, Costa C et al. 2013. KRAS mutations in lung cancer. Clin. Lung Cancer 14:205–14
    [Google Scholar]
  18. 18. 
    Prior IA, Lewis PD, Mattos C 2012. A comprehensive survey of Ras mutations in cancer. Cancer Res 72:2457–67
    [Google Scholar]
  19. 19. 
    AACR Project GENIE Consort 2017. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov 7:818–31
    [Google Scholar]
  20. 20. 
    Ostrem JM, Peters U, Sos ML et al. 2013. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548–51
    [Google Scholar]
  21. 21. 
    Milburn MV, Tong L, deVos AM et al. 1990. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247:939–45
    [Google Scholar]
  22. 22. 
    Hobbs GA, Wittinghofer A, Der CJ 2016. Selective targeting of the KRAS G12C mutant: kicking KRAS when it's down. Cancer Cell 29:251–53
    [Google Scholar]
  23. 23. 
    Visscher M, Arkin MR, Dansen TB 2016. Covalent targeting of acquired cysteines in cancer. Curr. Opin. Chem. Biol. 30:61–67
    [Google Scholar]
  24. 24. 
    Wilson CY, Tolias P. 2016. Recent advances in cancer drug discovery targeting RAS. Drug Discov. Today 21:1915–19
    [Google Scholar]
  25. 25. 
    Patricelli MP, Janes MR, Li LS et al. 2016. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:316–29
    [Google Scholar]
  26. 26. 
    Hunter JC, Gurbani D, Ficarro SB et al. 2014. In situ selectivity profiling and crystal structure of SML-8-73-1, an active site inhibitor of oncogenic K-Ras G12C. PNAS 111:8895–900
    [Google Scholar]
  27. 27. 
    Sun Q, Burke JP, Phan J et al. 2012. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew. Chem. Int. Ed. Engl. 51:6140–43
    [Google Scholar]
  28. 28. 
    Maurer T, Garrenton LS, Oh A et al. 2012. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. PNAS 109:5299–304
    [Google Scholar]
  29. 29. 
    Ostrem JM, Shokat KM. 2016. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Discov. 15:771–85
    [Google Scholar]
  30. 30. 
    Cruz-Migoni A, Canning P, Quevedo CE et al. 2019. Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. PNAS 116:2545–50
    [Google Scholar]
  31. 31. 
    Quevedo CE, Cruz-Migoni A, Bery N et al. 2018. Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat. Commun. 9:3169
    [Google Scholar]
  32. 32. 
    Okudela K, Woo T, Kitamura H 2010. KRAS gene mutations in lung cancer: particulars established and issues unresolved. Pathol. Int. 60:651–60
    [Google Scholar]
  33. 33. 
    Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA 2010. Personalized medicine in non-small-cell lung cancer: Is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy. J. Clin. Oncol. 28:4769–77
    [Google Scholar]
  34. 34. 
    Thu KL, Vucic EA, Chari R et al. 2012. Lung adenocarcinoma of never smokers and smokers harbor differential regions of genetic alteration and exhibit different levels of genomic instability. PLOS ONE 7:e33003
    [Google Scholar]
  35. 35. 
    Heinemann V, Stintzing S, Kirchner T et al. 2009. Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. Cancer Treat. Rev. 35:262–71
    [Google Scholar]
  36. 36. 
    Hayama T, Hashiguchi Y, Okamoto K et al. 2019. G12V and G12C mutations in the gene KRAS are associated with a poorer prognosis in primary colorectal cancer. Int. J. Colorectal Dis. 34:1491–96
    [Google Scholar]
  37. 37. 
    Cannataro VL, Gaffney SG, Stender C et al. 2018. Heterogeneity and mutation in KRAS and associated oncogenes: evaluating the potential for the evolution of resistance to targeting of KRAS G12C. Oncogene 37:2444–55
    [Google Scholar]
  38. 38. 
    Ricciuti B, Leonardi GC, Metro G et al. 2016. Targeting the KRAS variant for treatment of non-small cell lung cancer: potential therapeutic applications. Expert Rev. Respir. Med. 10:53–68
    [Google Scholar]
  39. 39. 
    Scheffler M, Ihle MA, Hein R et al. 2019. K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways. J. Thorac. Oncol. 14:606–16
    [Google Scholar]
  40. 40. 
    Sanchez-Vega F, Mina M, Armenia J et al. 2018. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell 173:321–37.e10
    [Google Scholar]
  41. 41. 
    Cancer Genome Atlas Netw 2012. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–37
    [Google Scholar]
  42. 42. 
    Schabath MB, Welsh EA, Fulp WJ et al. 2016. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene 35:3209–16
    [Google Scholar]
  43. 43. 
    Skoulidis F, Goldberg ME, Greenawalt DM et al. 2018. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 8:822–35
    [Google Scholar]
  44. 44. 
    Watanabe F, Suzuki K, Tamaki S et al. 2019. Longitudinal monitoring of KRAS-mutated circulating tumor DNA enables the prediction of prognosis and therapeutic responses in patients with pancreatic cancer. PLOS ONE 14:e0227366
    [Google Scholar]
  45. 45. 
    Wang ZY, Ding XQ, Zhu H et al. 2019. KRAS mutant allele fraction in circulating cell-free DNA correlates with clinical stage in pancreatic cancer patients. Front. Oncol. 9:1295
    [Google Scholar]
  46. 46. 
    Guo S, Shi X, Shen J et al. 2020. Preoperative detection of KRAS G12D mutation in ctDNA is a powerful predictor for early recurrence of resectable PDAC patients. Br. J. Cancer 122:857–67
    [Google Scholar]
  47. 47. 
    Groot VP, Mosier S, Javed AA et al. 2019. Circulating tumor DNA as a clinical test in resected pancreatic cancer. Clin. Cancer Res. 25:4973–84
    [Google Scholar]
  48. 48. 
    Bagchi S, Rathee P, Jayaprakash V, Banerjee S 2018. Farnesyl transferase inhibitors as potential anticancer agents. Mini Rev. Med. Chem. 18:1611–23
    [Google Scholar]
  49. 49. 
    Nussinov R, Jang H, Tsai CJ et al. 2017. Intrinsic protein disorder in oncogenic KRAS signaling. Cell. Mol. Life Sci. 74:3245–61
    [Google Scholar]
  50. 50. 
    Hampton SE, Dore TM, Schmidt WK 2018. Rce1: mechanism and inhibition. Crit. Rev. Biochem. Mol. Biol. 53:157–74
    [Google Scholar]
  51. 51. 
    Diver MM, Pedi L, Koide A et al. 2018. Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT. Nature 553:526–29
    [Google Scholar]
  52. 52. 
    Tanaka A, Radwan MO, Hamasaki A et al. 2017. A novel inhibitor of farnesyltransferase with a zinc site recognition moiety and a farnesyl group. Bioorg. Med. Chem. Lett. 27:3862–66
    [Google Scholar]
  53. 53. 
    Kazi A, Xiang S, Yang H et al. 2019. Dual farnesyl and geranylgeranyl transferase inhibitor thwarts mutant KRAS-driven patient-derived pancreatic tumors. Clin. Cancer Res. 25:5984–96
    [Google Scholar]
  54. 54. 
    Manandhar SP, Hildebrandt ER, Schmidt WK 2007. Small-molecule inhibitors of the Rce1p CaaX protease. J. Biomol. Screen. 12:983–93
    [Google Scholar]
  55. 55. 
    Mohammed I, Hampton SE, Ashall L et al. 2016. 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. Bioorg. Med. Chem. 24:160–78
    [Google Scholar]
  56. 56. 
    Marín-Ramos NI, Balabasquer M, Ortega-Nogales FJ et al. 2019. A potent isoprenylcysteine carboxylmethyltransferase (ICMT) inhibitor improves survival in Ras-driven acute myeloid leukemia. J. Med. Chem. 62:6035–46
    [Google Scholar]
  57. 57. 
    Manu KA, Chai TF, Teh JT et al. 2017. Inhibition of isoprenylcysteine carboxylmethyltransferase induces cell-cycle arrest and apoptosis through p21 and p21-regulated BNIP3 induction in pancreatic cancer. Mol. Cancer Ther. 16:914–23
    [Google Scholar]
  58. 58. 
    Cox AD, Fesik SW, Kimmelman AC et al. 2014. Drugging the undruggable RAS: mission possible. Nat. Rev. Drug Discov. 13:828–51
    [Google Scholar]
  59. 59. 
    Wahlstrom AM, Cutts BA, Karlsson C et al. 2007. Rce1 deficiency accelerates the development of K-RAS-induced myeloproliferative disease. Blood 109:763–68
    [Google Scholar]
  60. 60. 
    Court H, Amoyel M, Hackman M et al. 2013. Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression. J. Clin. Investig. 123:4681–94
    [Google Scholar]
  61. 61. 
    Hillig RC, Sautier B, Schroeder J et al. 2019. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. PNAS 116:2551–60
    [Google Scholar]
  62. 62. 
    Patgiri A, Yadav KK, Arora PS, Bar-Sagi D 2011. An orthosteric inhibitor of the Ras-Sos interaction. Nat. Chem. Biol. 7:585–87
    [Google Scholar]
  63. 63. 
    Li S, Liu S, Deng J et al. 2018. Assessing therapeutic efficacy of MEK inhibition in a KRASG12C-driven mouse model of lung cancer. Clin. Cancer Res. 24:4854–64
    [Google Scholar]
  64. 64. 
    Ambrogio C, Kohler J, Zhou ZW et al. 2018. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell 172:857–68.e15
    [Google Scholar]
  65. 65. 
    Lito P, Saborowski A, Yue J et al. 2014. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell 25:697–710
    [Google Scholar]
  66. 66. 
    Janne PA, van den Heuvel MM, Barlesi F et al. 2017. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA 317:1844–53
    [Google Scholar]
  67. 67. 
    Blumenschein GR Jr., Smit EF, Planchard D et al. 2015. A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC). Ann. Oncol. 26:894–901
    [Google Scholar]
  68. 68. 
    Manning BD, Toker A. 2017. AKT/PKB signaling: navigating the network. Cell 169:381–405
    [Google Scholar]
  69. 69. 
    McCubrey JA, Steelman LS, Abrams SL et al. 2006. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv. Enzyme Regul. 46:249–79
    [Google Scholar]
  70. 70. 
    Ihle NT, Lemos R Jr., Wipf P et al. 2009. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 69:143–50
    [Google Scholar]
  71. 71. 
    Kim JY, Welsh EA, Fang B et al. 2016. Phosphoproteomics reveals MAPK inhibitors enhance MET- and EGFR-driven AKT signaling in KRAS-mutant lung cancer. Mol. Cancer Res. 14:1019–29
    [Google Scholar]
  72. 72. 
    Engelman JA, Chen L, Tan X et al. 2008. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14:1351–56
    [Google Scholar]
  73. 73. 
    Misale S, Fatherree JP, Cortez E et al. 2019. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin. Cancer Res. 25:796–807
    [Google Scholar]
  74. 74. 
    Mendoza MC, Er EE, Blenis J 2011. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem. Sci. 36:320–28
    [Google Scholar]
  75. 75. 
    Wong GS, Zhou J, Liu JB et al. 2018. Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat. Med. 24:968–77
    [Google Scholar]
  76. 76. 
    Zhang J, Zhang F, Niu R 2015. Functions of Shp2 in cancer. J. Cell Mol. Med. 19:2075–83
    [Google Scholar]
  77. 77. 
    Hof P, Pluskey S, Dhe-Paganon S et al. 1998. Crystal structure of the tyrosine phosphatase SHP-2. Cell 92:441–50
    [Google Scholar]
  78. 78. 
    Mainardi S, Mulero-Sanchez A, Prahallad A et al. 2018. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat. Med. 24:961–67
    [Google Scholar]
  79. 79. 
    Kaelin WG Jr 2005. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5:689–98
    [Google Scholar]
  80. 80. 
    Puyol M, Martin A, Dubus P et al. 2010. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18:63–73
    [Google Scholar]
  81. 81. 
    de Castro Carpeno J, Belda-Iniesta C 2013. KRAS mutant NSCLC, a new opportunity for the synthetic lethality therapeutic approach. Transl. Lung Cancer Res. 2:142–51
    [Google Scholar]
  82. 82. 
    Corcoran RB, Do KT, Cleary JM et al. 2019. Phase I/II study of combined BCL-XL and MEK inhibition with navitoclax (N) and trametinib (T) in KRAS or NRAS mutant advanced solid tumours. Ann. Oncol. 30:v164
    [Google Scholar]
  83. 83. 
    Goldman JW, Mazieres J, Barlesi F et al. 2018. A randomized phase 3 study of abemaciclib versus erlotinib in previously treated patients with stage IV NSCLC with KRAS mutation: JUNIPER. J. Clin. Oncol. 36:9025
    [Google Scholar]
  84. 84. 
    Cancer Discovery 2019. AMG 510 first to inhibit “undruggable” KRAS. Cancer Discov 9:988–89
    [Google Scholar]
  85. 85. 
    Canon J, Rex K, Saiki AY et al. 2019. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575:217–23
    [Google Scholar]
  86. 86. 
    Fakih M, O'Neil B, Price TJ et al. 2019. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. J. Clin. Oncol. 37:3003
    [Google Scholar]
  87. 87. 
    Govindan R, Fakih MG, Price TJ et al. 2019. Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours. Ann. Oncol. 30:v163–v4
    [Google Scholar]
  88. 88. 
    Govindan R, Fakih M, Price T et al. 2019. OA02.02 phase 1 study of safety, tolerability, PK and efficacy of AMG 510, a novel KRASG12C inhibitor, evaluated in NSCLC. J. Thorac. Oncol. 14:S208
    [Google Scholar]
  89. 89. 
    Hallin J, Engstrom LD, Hargis L et al. 2020. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov 10:54–71
    [Google Scholar]
  90. 90. 
    Janne PA, Papadopoulos KP, Ou SI et al. 2019. A phase I clinical trial evaluating the pharmakokinetics (PK), safety, and clinical activity of MRTX849, a mutant-selective small molecule KRAS G12C inhibitor, in advanced solid tumors Paper presented at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Oct. 26–30 Boston, MA:
  91. 91. 
    Janes MR, Zhang J, Li LS et al. 2018. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172:578–89.e17
    [Google Scholar]
  92. 92. 
    Xue JY, Zhao Y, Aronowitz J et al. 2020. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 577:421–25
    [Google Scholar]
  93. 93. 
    Nagasaka M, Li Y, Sukari A et al. 2020. KRAS G12C game of thrones, which direct KRAS inhibitor will claim the iron throne. Cancer Treat. Rev. 84:101974
    [Google Scholar]
  94. 94. 
    Saltz LB, Meropol NJ, Loehrer PJ Sr. et al. 2004. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 22:1201–8
    [Google Scholar]
  95. 95. 
    Van Cutsem E, Peeters M, Siena S et al. 2007. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25:1658–64
    [Google Scholar]
  96. 96. 
    Díaz-Serrano A, Gella P, Jiménez E et al. 2018. Targeting EGFR in lung cancer: current standards and developments. Drugs 78:893–911
    [Google Scholar]
  97. 97. 
    Byeon HK, Ku M, Yang J 2019. Beyond EGFR inhibition: multilateral combat strategies to stop the progression of head and neck cancer. Exp. Mol. Med. 51:1–14
    [Google Scholar]
  98. 98. 
    Amodio V, Yaeger R, Arcella P et al. 2020. EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer. Cancer Discov 10:1129–39
    [Google Scholar]
  99. 99. 
    Kopetz S, Grothey A, Yaeger R et al. 2019. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N. Engl. J. Med. 381:1632–43
    [Google Scholar]
  100. 100. 
    Prahallad A, Sun C, Huang S et al. 2012. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483:100–3
    [Google Scholar]
  101. 101. 
    Hong DS, Morris VK, El Osta B et al. 2016. Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation. Cancer Discov 6:1352–65
    [Google Scholar]
  102. 102. 
    Hong DS, Fakih MG, Strickler JHet al 2020. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med 383:1207–17
    [Google Scholar]
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