Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

The AACR Project GENIE Consortium AACR project GENIE: powering precision medicine through an international consortium. Cancer Discov. 7, 818–831 (2017).

Article  PubMed Central  Google Scholar 

Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 47, D941–D947 (2019).

Article  CAS  PubMed  Google Scholar 

Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of Ras mutations in cancer. Cancer Res. 80, 2969–2974 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged? Nat. Rev. Drug. Discov. 19, 533–552 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Punekar, S. R., Velcheti, V., Neel, B. G. & Wong, K.-K. The current state of the art and future trends in RAS-targeted cancer therapies. Nat. Rev. Clin. Oncol. 19, 637–655 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Peters, S., Mok, T., Passaro, A. & Jänne, P. A. The promising evolution of targeted therapeutic strategies in cancer. Cancer Discov. 11, 810–814 (2021).

Article  CAS  PubMed  Google Scholar 

Konieczkowski, D. J., Johannessen, C. M. & Garraway, L. A. A convergence-based framework for cancer drug resistance. Cancer Cell 33, 801–815 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ryan, M. B. & Corcoran, R. B. Therapeutic strategies to target RAS-mutant cancers. Nat. Rev. Clin. Oncol. 15, 709–720 (2018).

Article  CAS  PubMed  Google Scholar 

Gysin, S., Salt, M., Young, A. & McCormick, F. Therapeutic strategies for targeting Ras proteins. Genes. Cancer 2, 359–372 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Karoulia, Z., Gavathiotis, E. & Poulikakos, P. I. New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer 17, 676–691 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, C. et al. RAF inhibitors that evade paradoxical MAPK pathway activation. Nature 526, 583–586 (2015).

Article  CAS  PubMed  Google Scholar 

Yao, Z. et al. RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat. Med. 25, 284–291 (2019).

Article  CAS  PubMed  Google Scholar 

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04916236 (2022).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05375994 (2023).

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).

Article  CAS  PubMed  Google Scholar 

Bhagwat, S. V. et al. ERK inhibitor LY3214996 targets ERK pathway-driven cancers: a therapeutic approach toward precision medicine. Mol. Cancer Ther. 19, 325–336 (2020).

Article  CAS  PubMed  Google Scholar 

Dombi, E. et al. Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. N. Engl. J. Med. 375, 2550–2560 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kun, E., Tsang, Y. T. M., Ng, C. W., Gershenson, D. M. & Wong, K. K. MEK inhibitor resistance mechanisms and recent developments in combination trials. Cancer Treat. Rev. 92, 102137 (2021).

Article  CAS  PubMed  Google Scholar 

Han, J. et al. MEK inhibitors for the treatment of non-small cell lung cancer. J. Hematol. Oncol. 14, 1 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-RasG12C inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013). This work is the first report of a direct KRAS-G12C small molecule inhibitor.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lim, S. M. et al. Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew. Chem. Int. Ed. Engl. 53, 199–204 (2014).

Article  CAS  PubMed  Google Scholar 

Skoulidis, F. et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N. Engl. J. Med. 384, 2371–2381 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jänne, P. A. et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N. Engl. J. Med. 387, 120–131 (2022).

Article  PubMed  Google Scholar 

Canon, J. et al. The clinical KRASG12C inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019).

Article  CAS  PubMed  Google Scholar 

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 (2020).

Article  CAS  PubMed  Google Scholar 

Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M. & Kraut, N. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 12, 924–937 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05379985 (2024).

Wang, X. et al. Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor. J. Med. Chem. 65, 3123–3133 (2022). This study describes the development of the first reported small molecule inhibitor with selective activity against KRAS-G12D and represents ongoing efforts to expand the druggable RAS repertoire beyond KRAS-G12C.

Article  CAS  PubMed  Google Scholar 

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05737706 (2023).

Zhou, C. et al. Design, synthesis, and biological evaluation of potent and selective PROTAC degraders of oncogenic KRASG12D. J. Med. Chem. 67, 1147–1167 (2024).

Article  CAS  PubMed  Google Scholar 

Tanaka, N. et al. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS–MAPK reactivation. Cancer Discov. 11, 1913–1922 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schulze, C. J. et al. Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS. Science 381, 794–799 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Molina-Arcas, M., Samani, A. & Downward, J. Drugging the undruggable: advances on RAS targeting in cancer. Genes 12, 899 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sacher, A. et al. Single-agent divarasib (GDC-6036) in solid tumors with a KRAS G12C mutation. N. Engl. J. Med. 389, 710–721 (2023).

Article  CAS  PubMed  Google Scholar 

Awad, M. M. et al. Acquired resistance to KRASG12C inhibition in cancer. N. Engl. J. Med. 384, 2382–2393 (2021). This study describes genetic alterations that mediate resistance in post-treatment tumours in patients treated with adagrasib.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhao, Y. et al. Diverse alterations associated with resistance to KRASG12C inhibition. Nature 599, 679–683 (2021). This study describes genetic alterations that mediate resistance in post-treatment tumours in patients treated with sotorasib.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Van Allen, E. M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2014).

Article