RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed ‘undruggable’. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRASG12C, we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS-mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Research progress on non-protein-targeted drugs for cancer therapy
Journal of Experimental & Clinical Cancer Research Open Access 14 March 2023
Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors
Scientific Reports Open Access 10 January 2023
An overview of PROTACs: a promising drug discovery paradigm
Molecular Biomedicine Open Access 20 December 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Amgen. Amgen Announces New Clinical Data Evaluating Novel Investigational KRAS(G12C) Inhibitor in Larger Patient Group at WCLC 2019 www.amgen.com https://www.amgen.com/media/news-releases/2019/09/amgen-announces-new-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-in-larger-patient-group-at-wclc-2019/ (2019).
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015).
Cancer Genome Atlas Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Cancer Genome Atlas Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203.e13 (2017).
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).
Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582 (2015).
Robertson, A. G. et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171, 540–556 (2017).
Haigis, K. M. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 40, 600–608 (2008).
Burd, C. E. et al. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov. 4, 1418–1429 (2014).
Laude, A. J. & Prior, I. A. Palmitoylation and localisation of RAS isoforms are modulated by the hypervariable linker domain. J. Cell Sci. 121, 421–427 (2008).
Tsai, F. D. et al. K-Ras4A splice variant is widely expressed in cancer and uses a hybrid membrane-targeting motif. Proc. Natl Acad. Sci. USA 112, 779–784 (2015).
McGrath, J. P. et al. Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature 304, 501–506 (1983).
Pells, S. et al. Developmentally-regulated expression of murine K-ras isoforms. Oncogene 15, 1781–1786 (1997).
Plowman, S. J. et al. K-ras 4A and 4B are co-expressed widely in human tissues, and their ratio is altered in sporadic colorectal cancer. J. Exp. Clin. Cancer Res. 25, 259–267 (2006).
Plowman, S. J. et al. While K-ras is essential for mouse development, expression of the K-ras 4A splice variant is dispensable. Mol. Cell. Biol. 23, 9245–9250 (2003).
Chen, W.-C. et al. Regulation of KRAS4A/B splicing in cancer stem cells by the RBM39 splicing complex. Preprint at bioRxiv https://doi.org/10.1101/646125 (2019).
Bonfini, L., Karlovich, C. A., Dasgupta, C. & Banerjee, U. The Son of sevenless gene product: a putative activator of Ras. Science 255, 603–606 (1992).
Buday, L. D. J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73, 611–620 (1993).
Ebinu, J. O. et al. RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Science 280, 1082–1086 (1998).
Xu, G. F. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608 (1990).
Trahey, M. M. F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238, 542–545 (1987).
Hunter, J. C. et al. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13, 1325–1335 (2015).
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).
Rabara, D. et al. KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. Proc. Natl Acad. Sci. USA 116, 22122–22131 (2019).
Johnson, L. et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 11, 2468–2481 (1997).
Nakamura, K. et al. Partial functional overlap of the three ras genes in mouse embryonic development. Oncogene 27, 2961–2968 (2008).
Potenza, N. et al. Replacement of K-Ras with H-Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice. EMBO Rep. 6, 432–437 (2005).
Gehringer, M. & Laufer, S. A. Emerging and re-emerging warheads for targeted covalent inhibitors: applications in medicinal chemistry and chemical biology. J. Med. Chem. 62, 5673–5724 (2019).
Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589 (2018).
Amgen. Amgen Announces New Clinical Data Evaluating Novel Investigational KRAS(G12C) Inhibitor in Patients with Solid Tumors at ESMO 2019 www.amgen.com https://www.amgen.com/media/news-releases/2019/09/amgen-announces-new-clinical-data-evaluating-novel-investigational-krasg12c-inhibitor-in-patients-with-solid-tumors-at-esmo-2019/ (2019).
Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019).
Mirati Therapeutics. Mirati Therapeutics Presents First Clinical Data of Phase 1/2 Trial of MRTX849 at the 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics ir.mirati.com https://ir.mirati.com/news-releases/news-details/2019/Mirati-Therapeutics-Presents-First-Clinical-Data-Of-Phase-12-Trial-Of-MRTX849-At-The-2019-AACR-NCI-EORTC-International-Conference-On-Molecular-Targets-And-Cancer-Therapeutics/default.aspx (2019).
Hallin, J. et al. The KRASG12C inhibitor, MRTX849, provides insight toward therapeutic susceptibility of KRAS mutant cancers in mouse models and patients. Cancer Discov. 10, 54–71 (2019).
Lito, P., Solomon, M., Li, L. S., Hansen, R. & Rosen, N. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Science 351, 604–608 (2016).
Patricelli, M. P. et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 6, 316–329 (2016).
Lou, K. et al. KRAS(G12C) inhibition produces a driver-limited state revealing collateral dependencies. Sci. Signal. 12, eaaw9450 (2019).
Gentile, D. R. et al. Ras binder induces a modified switch-II pocket in GTP and GDP states. Cell Chem. Biol. 24, 1455–1466 (2017).
Revolution Medicines. Revolution Medicines to Present Preclinical Data on Novel Inhibitors of Oncogenic RAS(ON) Mutants at AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics www.revmed.com https://www.revmed.com/media/revolution-medicines-present-preclinical-data-novel-inhibitors-oncogenic-rason-mutants-aacr (2019).
Welsch, M. E. et al. Multivalent small-molecule pan-RAS inhibitors. Cell 168, 878–889 (2017).
Drosten, M., Lechuga, C. G. & Barbacid, M. Ras signaling is essential for skin development. Oncogene 33, 2857–2865 (2014).
Drosten, M. et al. Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J. 29, 1091–1104 (2010).
Maurer, T. et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl Acad. Sci. USA 109, 5299–5304 (2012).
Cruz-Migoni, A. et al. Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. Proc. Natl Acad. Sci. USA 116, 2545–2550 (2019).
Quevedo, C. E. et al. Small molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment. Nat. Commun. 9, 3169 (2018).
Kessler, D. et al. Drugging an undruggable pocket on KRAS. Proc. Natl Acad. Sci. USA 116, 15823–15829 (2019).
Sun, Q. et al. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew. Chem. Int. Ed. Engl. 51, 6140–6143 (2012).
Leshchiner, E. S. et al. Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc. Natl Acad. Sci. USA 112, 1761–1766 (2015).
Patgiri, A., Yadav, K. K., Arora, P. S. & Bar-Sagi, D. An orthosteric inhibitor of the Ras-Sos interaction. Nat. Chem. Biol. 7, 585–587 (2011).
Winter, J. J. et al. Small molecule binding sites on the Ras:SOS complex can be exploited for inhibition of Ras activation. J. Med. Chem. 58, 2265–2274 (2015).
Burns, M. C. et al. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc. Natl Acad. Sci. USA 111, 3401–3406 (2014).
Hillig, R. C. et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc. Natl Acad. Sci. USA 116, 2551–2560 (2019).
Shi, Z. Q., Yu, D. H., Park, M., Marshall, M. & Feng, G. S. Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity. Mol. Cell. Biol. 20, 1526–1536 (2000).
Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 29, 465–468 (2001).
Castel, P. et al. RIT1 oncoproteins escape LZTR1-mediated proteolysis. Science 363, 1226–1230 (2019).
Rauen, K. A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 14, 355–369 (2013).
Dance, M., Montagner, A., Salles, J. P., Yart, A. & Raynal, P. The molecular functions of Shp2 in the Ras/mitogen-activated protein kinase (ERK1/2) pathway. Cell. Signal. 20, 453–459 (2008).
Li, W. et al. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol. Cell. Biol. 14, 509–517 (1994).
Bennett, A. M., Tang, T. L., Sugimoto, S., Walsh, C. T. & Neel, B. G. Protein-tyrosine-phosphatase SHPTP2 couples platelet-derived growth factor receptor beta to Ras. Proc. Natl Acad. Sci. USA 91, 7335–7339 (1994).
Ruess, D. A. et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat. Med. 24, 954–960 (2018).
Chen, Y. N. et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535, 148–152 (2016).
Lu, H. et al. SHP2 inhibition overcomes RTK-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors. Mol. Cancer Ther. 18, 1323–1334 (2019).
Nichols, R. J. et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat. Cell Biol. 20, 1064–1073 (2018).
Mirati Therapeutics. Mirati Announces Clinical Collaboration to Evaluate MRTX849 in Combination with SHP2 Inhibitor TNO155 ir.mirati.com https://ir.mirati.com/news-releases/news-details/2019/Mirati-Announces-Clinical-Collaboration-to-Evaluate-MRTX849-in-Combination-with-SHP2-Inhibitor-TNO155/default.aspx (2019).
Whyte, D. B. et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459–14464 (1997).
Kessler, L., Scholz, C., Gualberto, A., Liu, Y. & Burrows, F. Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models [abstract]. Cancer Res. 78 (Suppl. 13), 4917 (2018).
Ho, A. et al. Preliminary results from a phase 2 trial of tipifarnib in HRAS-mutant head and neck squamous cell carcinomas [abstract]. Int. J. Radiat. Oncol. Biol. Phys. 100, 1367 (2018).
Wang, T. et al. Gene essentiality profiling reveals gene networks and synthetic lethal interactions with oncogenic Ras. Cell 168, 890–903 (2017).
Winter-Vann, A. M. et al. A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc. Natl Acad. Sci. USA 102, 4336–4341 (2005).
Wang, M. et al. Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth. Oncogene 29, 4959–4970 (2010).
Manu, K. A. et al. Inhibition of isoprenylcysteine carboxylmethyltransferase induces cell-cycle arrest and apoptosis through p21 and p21-regulated BNIP3 induction in pancreatic cancer. Mol. Cancer Ther. 16, 914–923 (2017).
Judd, W. R. et al. Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT). J. Med. Chem. 54, 5031–5047 (2011).
Marin-Ramos, N. I. et al. A potent isoprenylcysteine carboxylmethyltransferase (ICMT) inhibitor improves survival in Ras-driven acute myeloid leukemia. J. Med. Chem. 62, 6035–6046 (2019).
Hampton, S. E., Dore, T. M. & Schmidt, W. K. Rce1: mechanism and inhibition. Crit. Rev. Biochem. Mol. Biol. 53, 157–174 (2018).
Mohammed, I. et al. 8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells. Bioorg. Med. Chem. 24, 160–178 (2016).
Chandra, A. et al. The GDI-like solubilizing factor PDEδ sustains the spatial organization and signalling of Ras family proteins. Nat. Cell Biol. 14, 148–158 (2011).
Zimmermann, G. et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature 497, 638–642 (2013).
Leung, E. L. et al. Identification of a new inhibitor of KRAS-PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer. Int. J. Cancer 145, 1334–1345 (2019).
Inouye, K., Mizutani, S., Koide, H. & Kaziro, Y. Formation of the Ras dimer is essential for Raf-1 activation. J. Biol. Chem. 275, 3737–3740 (2000).
Prior, I. A., Muncke, C., Parton, R. G. & Hancock, J. F. Direct visualization of Ras proteins in spatially distinct cell surface microdomains. J. Cell Biol. 160, 165–170 (2003).
Plowman, S. J., Muncke, C., Parton, R. G. & Hancock, J. F. H-ras, K-ras, and inner plasma membrane raft proteins operate in nanoclusters with differential dependence on the actin cytoskeleton. Proc. Natl Acad. Sci. USA 102, 15500–15505 (2005).
Abankwa, D., Gorfe, A. A., Inder, K. & Hancock, J. F. Ras membrane orientation and nanodomain localization generate isoform diversity. Proc. Natl Acad. Sci. USA 107, 1130–1135 (2010).
Solman, M. et al. Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation. Elife 4, e08905 (2015).
Tian, T. et al. Plasma membrane nanoswitches generate high-fidelity Ras signal transduction. Nat. Cell Biol. 9, 905–914 (2007).
Zhou, Y. & Hancock, J. F. Ras nanoclusters: versatile lipid-based signaling platforms. Biochim. Biophys. Acta 1853, 841–849 (2015).
Guldenhaupt, J. et al. N-Ras forms dimers at POPC membranes. Biophys. J. 103, 1585–1593 (2012).
Lin, W. C. et al. H-Ras forms dimers on membrane surfaces via a protein-protein interface. Proc. Natl Acad. Sci. USA 111, 2996–3001 (2014).
Muratcioglu, S. et al. GTP-dependent K-Ras dimerization. Structure 23, 1325–1335 (2015).
Nan, X. et al. Ras-GTP dimers activate the mitogen-activated protein kinase (MAPK) pathway. Proc. Natl Acad. Sci. USA 112, 7996–8001 (2015).
Prakash, P. et al. Computational and biochemical characterization of two partially overlapping interfaces and multiple weak-affinity K-Ras dimers. Sci. Rep. 7, 40109 (2017).
Sarkar-Banerjee, S. et al. Spatiotemporal analysis of K-Ras plasma membrane interactions reveals multiple high order homo-oligomeric complexes. J. Am. Chem. Soc. 139, 13466–13475 (2017).
Spencer-Smith, R. et al. Inhibition of RAS function through targeting an allosteric regulatory site. Nat. Chem. Biol. 13, 62–68 (2017).
Ambrogio, C. et al. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell 172, 857–868 (2018).
Khan, I., Spencer-Smith, R. & O’Bryan, J. P. Targeting the α4-α5 dimerization interface of K-RAS inhibits tumor formation in vivo. Oncogene 38, 2984–2993 (2019).
Fang, Z. et al. Inhibition of K-RAS4B by a unique mechanism of action: stabilizing membrane-dependent occlusion of the effector-binding site. Cell Chem. Biol. 25, 1327–1336 (2018).
Mazhab-Jafari, M. T. et al. Oncogenic and RASopathy-associated K-RAS mutations relieve membrane-dependent occlusion of the effector-binding site. Proc. Natl Acad. Sci. USA 112, 6625–6630 (2015).
Sanclemente, M. et al. c-RAF ablation induces regression of advanced Kras/Trp53 mutant lung adenocarcinomas by a mechanism independent of MAPK signaling. Cancer Cell 33, 217–228 (2018).
Blasco, M. T. et al. Complete regression of advanced pancreatic ductal adenocarcinomas upon combined inhibition of EGFR and C-RAF. Cancer Cell 35, 573–587 (2019).
Young, L. C. et al. SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis. Proc. Natl Acad. Sci. USA 115, E10576–E10585 (2018).
Jones, G. G. et al. SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers. Nat. Commun. 10, 2532 (2019).
Sulahian, R. et al. Synthetic lethal interaction of SHOC2 depletion with MEK inhibition in RAS-driven cancers. Cell Rep. 29, 118–134 (2019).
Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).
Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008).
Linardou, H. et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 9, 962–972 (2008).
Mao, C. et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 69, 272–278 (2010).
Pao, W. et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306–13311 (2004).
Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).
Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25, 1960–1966 (2007).
De Roock, W. et al. Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA 304, 1812–1820 (2010).
Peeters, M. et al. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J. Clin. Oncol. 31, 759–765 (2013).
Segelov, E. et al. ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours. BMC Cancer 16, 339 (2016).
Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).
Ardito, C. M. et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012).
Navas, C. et al. EGF receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012).
Moll, H. P. et al. Afatinib restrains K-RAS-driven lung tumorigenesis. Sci. Transl Med. 10, eaao2301 (2018).
Kruspig, B. et al. The ERBB network facilitates KRAS-driven lung tumorigenesis. Sci. Transl Med. 10, eaao2565 (2018).
Chen, H. Y. et al. EGFR-activating mutations, DNA copy number abundance of ErbB family, and prognosis in lung adenocarcinoma. Oncotarget 7, 9017–9025 (2016).
Dent, P. et al. Neratinib degrades MST4 via autophagy that reduces membrane stiffness and is essential for the inactivation of PI3K, ERK1/2, and YAP/TAZ signaling. J. Cell. Physiol. https://doi.org/10.1002/jcp.29443 (2020).
Sun, C. et al. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep. 7, 86–93 (2014).
Xie, Y. et al. COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors. J. Clin. Invest. 128, 1442–1457 (2018).
Dougherty, M. K. et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215–224 (2005).
Owens, D. M. & Keyse, S. M. Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26, 3203–3213 (2007).
Pratilas, C. A. et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc. Natl Acad. Sci. USA 106, 4519–4524 (2009).
Lake, D., Correa, S. A. & Muller, J. Negative feedback regulation of the ERK1/2 MAPK pathway. Cell. Mol. Life Sci. 73, 4397–4413 (2016).
Kim, H. J. & Bar-Sagi, D. Modulation of signalling by Sprouty: a developing story. Nat. Rev. Mol. Cell Biol. 5, 441–450 (2004).
Mason, J. M., Morrison, D. J., Basson, M. A. & Licht, J. D. Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol. 16, 45–54 (2006).
Karoulia, Z. et al. An integrated model of RAF inhibitor action predicts inhibitor activity against oncogenic BRAF signaling. Cancer Cell 30, 501–503 (2016).
Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464, 431–435 (2010).
Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464, 427–430 (2010).
Yen, I. et al. Pharmacological induction of RAS-GTP confers RAF inhibitor sensitivity in KRAS mutant tumors. Cancer Cell 34, 611–625 (2018).
Peng, S. B. et al. Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell 28, 384–398 (2015).
Nakamura, A. et al. Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res. 73, 7043–7055 (2013).
Wang, X. & Kim, J. Conformation-specific effects of Raf kinase inhibitors. J. Med. Chem. 55, 7332–7341 (2012).
Okaniwa, M. et al. Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives. J. Med. Chem. 56, 6478–6494 (2013).
Sun, Y. et al. A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol. 19, 774–785 (2017).
Vakana, E. et al. LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer. Oncotarget 8, 9251–9266 (2017).
Yao, Y. M. et al. Mouse PDX trial suggests synergy of concurrent inhibition of RAF and EGFR in colorectal cancer with BRAF or KRAS mutations. Clin. Cancer Res. 23, 5547–5560 (2017).
Kim, T. W. et al. Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: phase I study. J. Clin. Oncol. 37, 3000–3000 (2019).
Monaco, K.-A. et al. RAF inhibitor LXH254 effectively inhibits B-and-CRAF, but not ARAF [abstract]. Cancer Res. 79 (Suppl. 13), LB-144 (2019).
Sullivan, R. J. et al. A phase I study of LY3009120, a pan-RAF inhibitor, in patients with advanced or metastatic cancer. Mol. Cancer Ther. 19, 460–467 (2020).
Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).
Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).
Carter, C. A. et al. Selumetinib with and without erlotinib in KRAS mutant and KRAS wild-type advanced nonsmall-cell lung cancer. Ann. Oncol. 27, 693–699 (2016).
Janne, P. A. et al. 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, 1844–1853 (2017).
Hellmann, M. D. et al. Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors. Ann. Oncol. 30, 1134–1142 (2019).
Zimmer, L. et al. Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin. Cancer Res. 20, 4251–4261 (2014).
Blumenschein, G. R. Jr. et al. 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 (2015).
Friday, B. B. et al. BRAF V600E disrupts AZD6244-induced abrogation of negative feedback pathways between extracellular signal-regulated kinase and Raf proteins. Cancer Res. 68, 6145–6153 (2008).
Hatzivassiliou, G. et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 501, 232–236 (2013).
Lito, P. et al. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell 25, 697–710 (2014).
Ascierto, P. A. et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 14, 249–256 (2013).
Lebbe, C. et al. Pimasertib (PIM) versus dacarbazine (DTIC) in patients (pts) with cutaneous NRAS melanoma: a controlled, open-label phase II trial with crossover [abstract 1136P]. Ann. Oncol. 27 (Suppl. 6), vi389 (2016).
Van Cutsem, E. et al. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int. J. Cancer 143, 2053–2064 (2018).
Bodoky, G. et al. A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest. N. Drugs 30, 1216–1223 (2012).
Bennouna, J. et al. A phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest. N. Drugs 29, 1021–1028 (2011).
Hainsworth, J. D. et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J. Thorac. Oncol. 5, 1630–1636 (2010).
Morris, E. J. et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 3, 742–750 (2013).
Hatzivassiliou, G. et al. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol. Cancer Ther. 11, 1143–1154 (2012).
Chaikuad, A. et al. A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics. Nat. Chem. Biol. 10, 853–860 (2014).
Moschos, S. J. et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight 3, e92352 (2018).
He, Y. et al. Identification and validation of PROM1 and CRTC2 mutations in lung cancer patients. Mol. Cancer 13, 19 (2014).
Boga, S. B. et al. MK-8353: discovery of an orally bioavailable dual mechanism ERK inhibitor for oncology. ACS Med. Chem. Lett. 9, 761–767 (2018).
Merchant, M. et al. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors. PLoS One 12, e0185862 (2017).
Weekes, C. D. et al. A phase Ib study to evaluate the MEK inhibitor cobimetinib in combination with the ERK1/2 inhibitor GDC-0994 in patients with advanced solid tumors. Cancer Res. 77, CT107 (2017).
Varga, A. et al. A first-in-human phase I study to evaluate the ERK1/2 inhibitor GDC-0994 in patients with advanced solid tumors. Clin. Cancer Res. 26, 1229–1236 (2020).
Sullivan, R. J. et al. First-in-class ERK1/2 inhibitor ulixertinib (BVD-523) in patients with MAPK mutant advanced solid tumors: results of a phase I dose-escalation and expansion study. Cancer Discov. 8, 184–195 (2018).
Burrows, F. et al. KO-947, a potent ERK inhibitor with robust preclinical single agent activity in MAPK pathway dysregulated tumors [abstract]. Cancer Res. 77 (Suppl. 13), 5168 (2017).
Bhagwat, S. V. et al. Discovery of LY3214996, a selective and novel ERK1/2 inhibitor with potent antitumor activities in cancer models with MAPK pathway alterations [abstract]. Cancer Res. 77 (Suppl. 13), 4973 (2017).
Pant, S. et al. A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced (adv) cancer (CA) patients (pts) [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 3001 (2019).
Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).
Vanhaesebroeck, B. et al. P110δ, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl Acad. Sci. USA 94, 4330–4335 (1997).
Hirsch, E. et al. Central role for G protein-coupled phosphoinositide 3-kinase γ in inflammation. Science 287, 1049–1053 (2000).
Houslay, D. M. et al. Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells. Sci. Signal. 9, ra82 (2016).
Schmid, M. C. et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell 19, 715–727 (2011).
Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).
Aoki, M., Batista, O., Bellacosa, A., Tsichlis, P. & Vogt, P. K. The Akt kinase: molecular determinants of oncogenicity. Proc. Natl Acad. Sci. USA 95, 14950–14955 (1998).
Wang, Q. et al. PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. Cell Death Dis. 9, 739 (2018).
Mao, M. et al. Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clin. Cancer Res. 19, 657–667 (2012).
Wee, S. et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 69, 4286–4293 (2009).
Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14, 1351–1356 (2008).
Hoeflich, K. P. et al. Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer Res. 72, 210–219 (2012).
Shapiro, G. I. et al. Phase Ib study of the MEK inhibitor cobimetinib (GDC-0973) in combination with the PI3K inhibitor pictilisib (GDC-0941) in patients with advanced solid tumors. Invest. New Drugs 38, 419–432 (2020).
Bedard, P. L. et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin. Cancer Res. 21, 730–738 (2015).
Juric, D. et al. A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors [abstract]. J. Clin. Oncol. 32 (Suppl. 15), 9051 (2014).
Algazi, A. P. et al. A dual pathway inhibition strategy using BKM120 combined with vemurafenib is poorly tolerated in BRAF V600(E/K) mutant advanced melanoma. Pigment. Cell Melanoma Res. 32, 603–606 (2019).
Ebi, H. et al. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J. Clin. Invest. 121, 4311–4321 (2011).
Molina-Arcas, M., Hancock, D. C., Sheridan, C., Kumar, M. S. & Downward, J. Coordinate direct input of both KRAS and IGF1 receptor to activation of PI3 kinase in KRAS-mutant lung cancer. Cancer Discov. 3, 548–563 (2013).
Molina-Arcas, M. et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci. Transl Med. 11, eaaw7999 (2019).
Tolcher, A. W. et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother. Pharmacol. 75, 183–189 (2015).
Shoushtari, A. N. et al. A randomized phase 2 study of trametinib with or without GSK2141795 in patients with advanced uveal melanoma [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 9511 (2016).
Tolcher, A. W. et al. A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors. Ann. Oncol. 26, 58–64 (2015).
Mita, M. et al. Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors. Invest. N. Drugs 35, 616–626 (2017).
Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).
Ross, S. J. et al. Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. Sci. Transl Med. 9, eaal5253 (2017).
Golan, T. et al. RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget 6, 24560–24570 (2015).
Kinsey, C. G. et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 25, 620–627 (2019).
Bryant, K. L. et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat. Med. 25, 628–640 (2019).
Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).
Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).
Wolpin, B. M. et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 19, 637–638 (2014).
White, N. J. The treatment of malaria. N. Engl. J. Med. 335, 800–806 (1996).
Boone, B. A. et al. Safety and biologic response of pre-operative autophagy inhibition in combination with gemcitabine in patients with pancreatic adenocarcinoma. Ann. Surg. Oncol. 22, 4402–4410 (2015).
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Eggermont, A. M. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N. Engl. J. Med. 375, 1845–1855 (2016).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med. 381, 2020–2031 (2019).
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
Weber, J. S. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375–384 (2015).
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).
Weber, J. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N. Engl. J. Med. 377, 1824–1835 (2017).
Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
Ribas, A. et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 16, 908–918 (2015).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
Rittmeyer, A. et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389, 255–265 (2017).
Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).
Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).
Sullivan, R. J. et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat. Med. 25, 929–935 (2019).
Keilholz, U. et al. Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN solid tumor trial. J. Immunother. Cancer 7, 12 (2019).
Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
Keenan, T. E., Burke, K. P. & Van Allen, E. M. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 25, 389–402 (2019).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Vonderheide, R. H. & Bayne, L. J. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr. Opin. Immunol. 25, 200–205 (2013).
Royal, R. E. et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).
Patnaik, A. et al. Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin. Cancer Res. 21, 4286–4293 (2015).
O’Reilly, E. M. et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 5, 1431–1438 (2019).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Overman, M. J. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017).
Eatrides, J. M. et al. Microsatellite instability in pancreatic cancer [abstract]. J. Clin. Oncol. 34 (Suppl. 15), e15753 (2016).
Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl Med. 8, 328rv324 (2016).
Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).
Coelho, M. A. et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity 47, 1083–1099 (2017).
Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).
Robbins, P. F. et al. A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 183, 1185–1192 (1996).
Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).
Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).
Veatch, J. R. et al. Endogenous CD4+ T cells recognize neoantigens in lung cancer patients, including recurrent oncogenic KRAS and ERBB2 (Her2) driver mutations. Cancer Immunol. Res. 7, 910–922 (2019).
Wang, Q. J. et al. Identification of T-cell receptors targeting KRAS-mutated human tumors. Cancer Immunol. Res. 4, 204–214 (2016).
Gjertsen, M. K. et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma. Int. J. Cancer 92, 441–450 (2001).
Palmer, D. H., Dueland, S., Valle, J. W. & Aksnes, A.-K. A phase I/II trial of TG01/GM-CSF and gemcitabine as adjuvant therapy for treating patients with resected RAS-mutant adenocarcinoma of the pancreas [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 4119 (2017).
Merck. Moderna and Merck expand mRNA cancer vaccines collaboration merck.com https://investors.merck.com/news/press-release-details/2018/Moderna-and-Merck-Expand-mRNA-Cancer-Vaccines-Collaboration/default.aspx (Merck, 2018).
Van Cutsem, E. et al. Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E-mutant metastatic colorectal cancer: safety lead-in results from the phase III BEACON colorectal cancer study. J. Clin. Oncol. 37, 1460–1469 (2019).
Xue, J. Y. et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 577, 421–425 (2020).
Sharma, S. V., Bell, D. W., Settleman, J. & Haber, D. A. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169–181 (2007).
Schwartz, P. A. et al. Covalent EGFR inhibitor analysis reveals importance of reversible interactions to potency and mechanisms of drug resistance. Proc. Natl Acad. Sci. USA 111, 173–178 (2014).
Yaeger, R. et al. Mechanisms of acquired resistance to BRAF V600E inhibition in colon cancers converge on RAF dimerization and are sensitive to its inhibition. Cancer Res. 77, 6513–6523 (2017).
Johnson, D. B. et al. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur. J. Cancer 51, 2792–2799 (2015).
Van Allen, E. M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2013).
Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).
Bean, J. et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl Acad. Sci. USA 104, 20932–20937 (2007).
Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).
Emery, C. M. et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl Acad. Sci. USA 106, 20411–20416 (2009).
Villanueva, J. et al. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 4, 1090–1099 (2013).
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).
Yu, H. A. et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 19, 2240–2247 (2013).
Johannessen, C. M. et al. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature 504, 138–142 (2013).
Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).
Thomson, S. et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res. 65, 9455–9462 (2005).
Frederick, B. A. et al. Epithelial to mesenchymal transition predicts gefitinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol. Cancer Ther. 6, 1683–1691 (2007).
Caramel, J. et al. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24, 466–480 (2013).
Richard, G. et al. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Mol. Med. 8, 1143–1161 (2016).
Whittaker, S. R. et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 3, 350–362 (2013).
The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 7, 818–831 (2017).
F.McC. is a consultant for the following companies: Amgen, Pfizer Inc., and Quanta Therapeutics; is a consultant and co-founder with ownership interest including stock options of BridgeBio Pharma, Inc; and is Scientific Director of the NCI Ras Initiative at Frederick National Laboratory for Cancer Research/Leidos Biomedical Research Inc. S.M. is an employee of Genentech/Roche. A.R.M. and S.C.R. are also post-doctoral fellows employed by Genentech/Roche.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
DepMap portal: depmap.org
Project GENIE: https://genie.cBioPortal.org
RCSB Protein Data Bank: https://www.rcsb.org/
A site that is outside the active site of an enzyme.
A group of clinically defined genetic syndromes caused by germline mutations of regulators or components of the MAPK pathway.
- Noonan syndrome
An autosomal dominant RASopathy characterized by distinctive craniofacial features. Frequently germline mutated genes in Noonan syndrome include PTPN11, SOS1, RAF1, KRAS, NRAS, MRAS, SHOC2, CBL and RIT1.
Rights and permissions
About this article
Cite this article
Moore, A.R., Rosenberg, S.C., McCormick, F. et al. RAS-targeted therapies: is the undruggable drugged?. Nat Rev Drug Discov 19, 533–552 (2020). https://doi.org/10.1038/s41573-020-0068-6
This article is cited by
Research progress on non-protein-targeted drugs for cancer therapy
Journal of Experimental & Clinical Cancer Research (2023)
Nanoformulation of the K-Ras(G12D)-inhibitory peptide KS-58 suppresses colorectal and pancreatic cancer-derived tumors
Scientific Reports (2023)
143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models
Acta Pharmacologica Sinica (2023)
RASON, a new player in cancer’s Premier League
Cell Research (2023)
LncRNA FAM83H-AS1 promotes the malignant progression of pancreatic ductal adenocarcinoma by stabilizing FAM83H mRNA to protect β-catenin from degradation
Journal of Experimental & Clinical Cancer Research (2022)