Metabolic adaptations to MEK and CDK4/6 co-targeting in uveal melanoma.

Frequent GNAQ and GNA11 mutations in uveal melanoma (UM) hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin dependent kinases (CDK) and cell cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in UM, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in ER-positive breast cancer patients in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in UM. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell cycle proteins. By contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased UM cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in UM and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.