Dual-MEK Inhibitor Atebimetinib Displays Broad Activity in RAS- and RAF-Mutant Tumors via Deep Cyclic Inhibition and Resisting RAF Bypass.

Inappropriate activation of the mitogen-activated protein kinase (MAPK) pathway, often stemming from activating mutations in RAS or RAF, represents one of the most common oncogenic events in human cancer. However, currently approved RAS/RAF inhibitors target specific mutants that are only present in a small proportion of RAS- or RAF-activated tumors. Current MEK inhibitors (MEKi) are associated with class-effect toxicities and tumor escape via CRAF bypass of MEK blockade. To address these issues, we designed atebimetinib to resist CRAF-mediated bypass and enable a pharmacokinetic/pharmacodynamic profile termed deep cyclic inhibition (DCI), an approach that transiently but deeply suppresses oncogenic signaling while allowing daily physiologic reset. Unlike chronic or intermittent approaches, DCI optimizes depth and duration of MEK suppression on a daily cycle, blunting rebound signaling while preserving recovery windows for normal tissues. Functioning as an allosteric, selective MEKi, atebimetinib potently inhibited ERK phosphorylation in vitro and in vivo, resisted CRAF bypass, and was well tolerated and more efficacious in xenograft models of cancer compared with current MEKis. Overall, these findings establish atebimetinib as a dual-MEKi with the potential to provide mutation-agnostic inhibition of the MAPK pathway while leveraging DCI, designed to avoid toxicities associated with existing MEKis. Atebimetinib offers MEK inhibition that is durable and tolerable, supporting the potential of this therapeutic paradigm. SIGNIFICANCE: Atebimetinib, a deep cyclic inhibitor of MEK, blocks MAPK signaling, resists RAF bypass, and is active in RAS- and RAF-mutant tumors, representing a mechanistically differentiated approach in the field of targeted therapies. See related commentary by Gaire and Poulikakos, p. 5017.