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Acquired Resistance to KRASG12C Inhibition in Cancer

Mark M Awad1, Shengwu Liu1, Igor I Rybkin1

  • 1From Dana-Farber Cancer Institute (M.M.A., S.L., J.D., J.O.J., K.E.L., H.F., K.M.H., B.M.W., P.A.J., A.J.A.), Massachusetts General Hospital (R.S.H., Y.P.H.), and Brigham and Women's Hospital (L.M.S., A.J.A.), Boston, and Broad Institute of MIT and Harvard (S.L., X.Y., N.S.P., D.E.R., K.M.H., A.J.A.) and Foundation Medicine (J.L., A.B.S.), Cambridge - all in Massachusetts; Henry Ford Cancer Institute, Detroit (I.I.R.); Memorial Sloan Kettering Cancer Center, New York (K.C.A., G.J.R., P.L.); Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Orange (V.W.Z., S.S.Z., S.-H.I.O.), Boundless Bio, La Jolla (J.W., J.C.), and Mirati Therapeutics, San Diego (L.D.E., L.W., J.D.L., P.O., J.G.C.) - all in California; Sarah Cannon Research Institute, Tennessee Oncology/OneOncology, Nashville (M.L.J.); the University of Colorado, Aurora (T.P.); and Resolution Bioscience, Kirkland, WA (L.P.L., K.G., M.L.).

The New England Journal of Medicine
|June 23, 2021
PubMed
Abstract

Insights

Resistance to KRAS G12C inhibitors like adagrasib emerges through diverse genetic alterations and histologic changes. Understanding these mechanisms is crucial for developing new strategies to overcome drug resistance in cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS G12C inhibitors (adagrasib, sotorasib) show promise in clinical trials for KRAS G12C-mutant cancers.
  • Mechanisms of acquired resistance to these targeted therapies remain largely unknown.

Purpose of the Study:

  • To investigate the genomic and histologic mechanisms of acquired resistance to adagrasib monotherapy in KRAS-mutant cancers.
  • To identify specific mutations and alterations that confer resistance to KRAS G12C inhibitors.

Main Methods:

  • Genomic and histologic analyses of pretreatment and post-resistance samples from patients treated with adagrasib.
  • Cell-based experiments utilizing deep mutational scanning to define resistance-conferring KRAS mutations.

Main Results:

  • Resistance mechanisms were identified in 45% of patients, with 18% exhibiting multiple mechanisms.
  • Acquired KRAS alterations (e.g., G12D/R/V/W, G13D) and bypass pathways (e.g., MET amplification, NRAS/BRAF mutations) were observed.
  • Histologic transformation to squamous-cell carcinoma occurred in some lung adenocarcinoma patients.

Conclusions:

  • Diverse genomic and histologic mechanisms contribute to resistance against covalent KRAS G12C inhibitors.
  • New therapeutic strategies are essential to delay and overcome acquired drug resistance in cancer treatment.

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