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Review
. 2021 Jun;11(6):1345-1352.
doi: 10.1158/2159-8290.CD-20-1616. Epub 2021 Apr 5.

Mechanisms of Resistance to KRASG12C-Targeted Therapy

Neal S Akhave  1 , Amadeo B Biter  2 , David S Hong  3
Affiliations
Review

Mechanisms of Resistance to KRASG12C-Targeted Therapy

Neal S Akhave et al. Cancer Discov. 2021 Jun.

Abstract

KRAS mutations are among the most common drivers of human carcinogenesis, and are associated with poor prognosis and an aggressive disease course. With the advent of KRASG12C inhibitors, the RAS protein is now targetable, with such inhibitors showing marked clinical responses across multiple tumor types. However, these responses are short-lived due to the development of resistance. Preclinical studies now suggest MAPK reactivation, stimulation of CDK4/6-dependent cell-cycle transition, and immune defects as possible mechanisms of resistance. Devising strategies to overcome such resistance mechanisms, which are a barrier to long-term clinical response, remain an active area of research. SIGNIFICANCE: Although KRAS-targeted cancer therapy is revolutionary, tumors rapidly develop resistance. Understanding the mechanisms driving this resistance and designing combination strategies to overcome it are integral to achieving long-term disease control.

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Figures

Figure 1.
Figure 1.
KRAS signaling, mechanisms of resistance to KRASG12C drugs, and targeted therapies.
See this image and copyright information in PMC

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