Metabolic adaptations to MEK and CDK4/6 cotargeting in uveal melanoma

Jessica L.F. Teh, Timothy J. Purwin, Anna Han, Vivian Chua, Prem Patel, Usman Baqai, Connie Liao, Nelisa Bechtel, Takami Sato, Michael A. Davies, Julio Aguirre-Ghiso, Andrew E. Aplin

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Frequent GNAQ and GNA11 mutations in uveal melanoma 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 uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)–positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In 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 uveal melanoma cell survival in combination with MEKi þ CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi þ CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.

Original languageEnglish
Pages (from-to)1719-1726
Number of pages8
JournalMolecular Cancer Therapeutics
Volume19
Issue number8
DOIs
StatePublished - 1 Aug 2020

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