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Study Provides Insight Into Overcoming Acquired Resistance to KRAS-G12C Inhibitors

Key findings

  • This study explored mechanisms of acquired resistance to adagrasib and similar drugs being developed for the treatment of non-small cell lung cancer (NSCLC) and other solid tumors harboring a KRASG12C mutation
  • Characterization of a patient with KRASG12C–mutant NSCLC who developed acquired resistance to adagrasib revealed the emergence of 10 individual resistance alterations involving four RAS–MAPK pathway genes
  • All of these alterations converged to reactivate RAS–MAPK signaling, suggesting this signaling may be a central mechanism of acquired resistance
  • Y96D, a previously unidentified secondary KRAS resistance mutation, conferred resistance to multiple KRASG12C inhibitors
  • RM-018, a novel KRASG12C inhibitor with a distinct mechanism of action for targeting KRAS, was able to overcome KRASG12C/Y96D across multiple models

In May 2021, the FDA approved sotorasib for patients with advanced non–small cell lung cancer (NSCLC) who carry the KRASG12C mutation, a target long considered undruggable. Adagrasib, another KRASG12C inhibitor, is still investigational but has received the breakthrough therapy designation.

Experience with other targeted therapies for solid tumors suggests that acquired resistance to KRASG12C inhibitors is inevitable. Jessica J. Lin, MD, an attending physician in the Center for Thoracic Cancers and the Termeer Center for Targeted Therapies at the Massachusetts General Hospital Cancer Center, Noritaka Tanaka, PhD, research fellow, and Chendi Li, PhD, research fellow, Aaron Hata, MD, PhD, an investigator in the Center for Cancer ResearchRebecca Heist, MD, MPH, an attending physician in the Center for Thoracic Cancers and the Termeer Center for Targeted Therapy, and Ryan Corcoran, MD, PhD, director of the Gastrointestinal Cancer Center Program and scientific director of the Termeer Center, and colleagues discovered a central mechanism of this resistance—and a drug that overcomes one resistance mutation. Their report appears in Cancer Discovery.

Case Report

The researchers studied a patient with advanced NSCLC who received adagrasib in a phase 1 trial. They sequenced cell-free DNA before treatment, during the response, and after resistance developed. They identified ten distinct resistance alterations that involved four RAS–MAPK genes, which converged to reactivate RAS–MAPK signaling.

The Y96D Mutation

One of the resistance alterations was Y96D, a previously unidentified secondary mutation in KRAS that alters drug binding. In the laboratory, cells expressing KRASG12C/Y96D showed marked resistance to sotorasib, adagrasib, and ARS-1620, another KRASG12C inhibitor in development, suggesting drug class–wide vulnerability to this mutation.


The researchers then tested RM-018, a novel KRASG12C inhibitor that has a markedly different mechanism of action—it binds specifically to the active ("RAS[ON]") state of KRASG12C. In multiple models, RM-018 was able to bind and inhibit KRASG12C/Y96D.

Therapeutic Implications

It will be necessary to develop novel compounds that target resistance after an acquired KRAS mutation emerges on the initial KRASG12C inhibitor. The findings of this study will help direct the rational design of those next-generation inhibitors.

However, the abundance of mutations downstream of RAS suggests MAPK reactivation alone may be sufficient to drive resistance in at least some KRASG12C-mutant cancers. Combining KRASG12C inhibitors with downstream MAPK pathway inhibitors may be necessary to prevent or overcome resistance.

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