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David S. Ettinger, MD, FACP, FCCP


Understanding Resistance to KRAS Inhibitors in Patients With NSCLC

By: Joseph Fanelli
Posted: Wednesday, March 16, 2022

Although clinical resistance to treatment with KRAS G12C inhibitors in patients with KRAS G12C–mutant non–small cell lung cancer (NSCLC) is not fully understood, initial reports indicate the acquired mechanisms of resistance are complex, heterogeneous, and may emerge concomitantly during treatment, according to a review presented in Frontiers in Oncology. For instance, disease progression following treatment with these inhibitors is caused by on-target mutations affecting the docking site of the inhibitor, other activating KRAS mutations, and activation of the canonical pathways by mutations, among other factors, explained Gonzalo Recondo, MD, PhD, of the Center for Medical Education and Clinical Research, Buenos Aires, and colleagues.

“Given the recent clinical approval of specific KRAS G12C inhibitors and the ongoing development of other strategies to target other KRAS mutations, understanding the biological mechanisms that confer primary and acquired resistance is necessary to improve patients’ clinical outcomes to the response rates and progression-free survival,” the authors concluded.

The authors focused on recent literature regarding the intrinsic and acquired mechanisms of resistance to KRAS G12C inhibitors in patients with mutant NSCLC. Clinical evidence evaluating KRAS G12C inhibitors such as sotorasib and adagrasib found that many patients do not experience a tumor response or primary disease progression; in fact, they added, unlike with other targeted therapies, patients who have KRAS mutations and initially achieve a partial response to KRAS G12C inhibitors seem to have a shorter duration of response because of acquired resistance mechanisms.

In general, the authors observed, biologic mechanisms of resistance can be divided into two groups: on-target resistance and off-target, or bypass, mechanisms. The former is driven by mutations or amplifications in the KRAS gene that curb drug binding, whereas the latter occurs when KRAS is inhibited, but another effector commands oncogenic signaling.

Future studies should explore resistance mechanisms in patients who experience a more extended benefit with KRAS G12C inhibitors, the authors proposed. Liquid biopsy next-generation sequencing is a “useful tool,” they added, to identify patients’ heterogeneity of resistance mechanisms.

Disclosure: For full disclosures of the study authors, visit

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