Acquired Resistance to KRAS Inhibition in Cancer.

N Engl J Med
Authors
Keywords
Abstract

BACKGROUND: 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). The mechanisms of acquired resistance to these therapies are currently unknown.

METHODS: Among patients with -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 inhibitors.

RESULTS: 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 alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the allele. Acquired bypass mechanisms of resistance included amplification; activating mutations in , , , and ; oncogenic fusions involving , , , , and ; and loss-of-function mutations in and . 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 mutations that confer resistance to KRAS inhibitors.

CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS 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.).

Year of Publication
2021
Journal
N Engl J Med
Volume
384
Issue
25
Pages
2382-2393
Date Published
2021 06 24
ISSN
1533-4406
DOI
10.1056/NEJMoa2105281
PubMed ID
34161704
Links
Grant list
1R01CA230267-01A1 / CA / NCI NIH HHS / United States
R01 CA230267 / CA / NCI NIH HHS / United States
19-029 MIA / Mark Foundation For Cancer Research
K08 CA218420-02 / CA / NCI NIH HHS / United States
1R01CA230745-01 / CA / NCI NIH HHS / United States
R01 CA230745 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
U01 CA210171 / CA / NCI NIH HHS / United States
CRP-17-111-01-CDD / American Cancer Society