The Next Generation of KRAS Targeting: Reasons for Excitement and Concern

The development of selective KRAS^G12C inhibitors that directly inhibit KRAS, an oncogene historically thought to be “undruggable,” represents a watershed moment in oncology and developmental therapeutics. Now, as KRAS-targeted therapy moves into its second phase, there is significant excitement and anticipation for durable disease control in tumor types where options remain limited, with clinical trials testing combination therapies, indirect pan-RAS/MAP kinase pathway inhibitors, and active-state RAS (on) inhibitors. However, there is also reason for caution regarding the safety and tolerability of expanded RAS inhibition. This is evidenced by the intolerability of some combination therapies with selective KRAS^G12C inhibitors and foreshadowed by prior failures of combination therapies in other oncogene-driven tumors. Herein, we review the landscape of and outlook for KRAS-targeted therapies. We specifically focus upon strategies to combat resistance to KRAS-targeted therapies, and discuss the possibility of off-target or unanticipated on-target effects that may limit clinical use.