Conquering oncogenic KRAS and its bypass mechanisms

Aberrant activation of KRAS signaling is common in cancer, which has catalyzed heroic drug development efforts to target KRAS directly or its downstream signaling effectors. Recent works have yielded novel small molecule drugs with promising preclinical and clinical activities. Yet, no matter how a cancer is addicted to a specific target ??? cancer???s genetic and biological plasticity fashions a variety of resistance mechanisms as a fait accompli, limiting clinical benefit of targeted interventions. Knowledge of these mechanisms may inform combination strategies to attack both oncogenic KRAS and subsequent bypass mechanisms.