The combination of KRASG12C and EGFR inhibitors allows for the targeting of KRAS mutations in colorectal cancer, but acquired resistance limits the duration of response. Yaeger and colleagues characterized mechanisms of resistance to KRASG12C plus EGFR inhibitors and found that heterogenous resistance changes largely converge on reactivation of ERK signaling. Moreover, KRASG12C amplification is a recurrent resistance mechanism that is positively selected for with treatment. When treatment is stopped, the acquired KRASG12C amplification leads to oncogene-induced senescence due to supraphysiologic ERK signaling and high mTOR signaling, opening the potential for new therapeutic approaches targeting this senescence.

See article, p. 41.

The tumor suppressor/transcription factor p53 is the most frequently mutated and inactivated gene in cancer. The p53 Y220C mutation occurs in 1% of patients and results in a thermally unstable protein that unfolds at physiologic temperatures. In this study, Guiley and Shokat discovered compounds that covalently...

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