Supplemental Figure 1. CDK4/6i + MEKi treatment does not modulate proteins within the apoptotic signaling pathway. Supplemental Figure 2. Growth of UM001 xenografts treated with MEKi and/or CDK4/6i. Supplemental Figure 3. RNA-seq samples cluster based treatment. Supplemental Figure 4. MEKi, CDK4/6i, and OxPhosi have reversible effects. Supplemental Figure 5. Cleaved caspase 3 staining in UM001 xenograft tumors.
ARTICLE 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 + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.
