Acquired Resistance to KRAS^G12C Inhibition in Cancer.

Abstract

Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS^G12C). The mechanisms of acquired resistance to these therapies are currently unknown. Among patients with <i>KRAS^G12C</i> -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS^G12C inhibitors. A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired <i>KRAS</i> alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the <i>KRAS^G12C</i> allele. Acquired bypass mechanisms of resistance included <i>MET</i> amplification; activating mutations in <i>NRAS</i>, <i>BRAF</i>, <i>MAP2K1</i>, and <i>RET</i>; oncogenic fusions involving <i>ALK</i>, <i>RET</i>, <i>BRAF</i>, <i>RAF1</i>, and <i>FGFR3</i>; and loss-of-function mutations in <i>NF1</i> and <i>PTEN</i>. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of <i>KRAS</i> mutations that confer resistance to KRAS^G12C inhibitors. Diverse genomic and histologic mechanisms impart resistance to covalent KRAS^G12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.).