KRAS G12C -independent feedback activation of wild-type RAS constrains KRAS G12C inhibitor efficacy.

Although KRAS has long been considered undruggable, direct KRAS ^G12C inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear. We find that upstream feedback activation of wild-type RAS, as opposed to a shift in KRAS ^G12C to its active guanosine triphosphate (GTP)-bound state, is sufficient to drive RAS-MAPK reactivation in a KRAS ^G12C -independent manner. Moreover, multiple receptor tyrosine kinases (RTKs) can drive feedback reactivation, potentially necessitating targeting of convergent signaling nodes for more universal efficacy. Even in colorectal cancer, where feedback is thought to be primarily epidermal growth factor receptor (EGFR)-mediated, alternative RTKs drive pathway reactivation and limit efficacy, but convergent upstream or downstream signal blockade can enhance activity. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting KRAS.
Competing Interests: Declaration of interests R.B.C. has received consulting or speaking fees from Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, AstraZeneca, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Cogent Biosciences, Elicio, Erasca, Fog Pharma, Genentech, Guardant Health, Ipsen, Kinnate Biopharma, LOXO, Merrimack, Mirati Therapeutics, Natera, Navire, Nested Therapeutics, N-of-one/Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roche, Roivant, Shionogi, Shire, Spectrum Pharmaceuticals, Symphogen, Syndax, Tango Therapeutics, Taiho, Theonys, Warp Drive Bio, and Zikani Therapeutics; holds equity in Alterome Therapeutics, Avidity Biosciences, C4 Therapeutics, Cogent Biosciences, Erasca, Kinnate Biopharma, Nested Therapeutics, nRichDx, Remix Therapeutics, Revolution Medicines, and Theonys; and has received research funding from Asana, AstraZeneca, Lilly, Novartis, and Sanofi. L.Z. and Y.Z. are employees and hold equity in Eli Lilly. SK. has received consulting or advisory fees from Genentech, EMD Serono, Merck, Holy Stone, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, Abbvie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therapeutics, Endeavor BioMedicines, Numab Pharma, and Johnson & Johnson/Janssen.
(Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)