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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

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Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma

Jessica L F Teh1, Timothy J Purwin1, Anna Han1

  • 1Department of Cancer Biology, Philadelphia, Pennsylvania.

Molecular Cancer Therapeutics
|May 21, 2020
PubMed

Insights

Frequent GNAQ/GNA11 mutations in uveal melanoma activate MEK-ERK signaling. Combining MEK inhibitors with CDK4/6 inhibitors revealed adaptive upregulation of oxidative phosphorylation, suggesting a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Uveal melanoma (UM) is driven by GNAQ/GNA11 mutations, leading to MEK-ERK pathway hyperactivation and cell-cycle dysregulation.
  • MEK inhibitors (MEKi) show limited efficacy in UM, necessitating exploration of vertical inhibition strategies.
  • CDK4/6 inhibitors (CDK4/6i) are effective in ER-positive breast cancer, suggesting potential in other malignancies.

Purpose of the Study:

  • To investigate the efficacy of combined MEK inhibitors (MEKi) and CDK4/6 inhibitors (CDK4/6i) in uveal melanoma.
  • To identify resistance mechanisms and potential therapeutic vulnerabilities associated with this combination therapy.

Main Methods:

  • In vitro and in vivo studies using uveal melanoma models.
  • Treatment with MEKi (trametinib) and CDK4/6i (palbociclib).
  • RNA sequencing, oxygen consumption rate measurements, and oxidative phosphorylation (OxPhos) inhibitor (IACS-010759) treatment.

Main Results:

  • In vitro, CDK4/6i enhanced MEKi efficacy by downregulating cell-cycle proteins.
  • In vivo, CDK4/6i monotherapy achieved cytostasis comparable to combination therapy in delaying tumor growth.
  • Both MEKi-resistant and CDK4/6i-tolerant tumors exhibited OxPhos pathway upregulation, with increased oxygen consumption.
  • Combined MEKi + CDK4/6i treatment led to adaptive OxPhos upregulation.
  • OxPhos inhibition with IACS-010759 sensitized UM cells to MEKi + CDK4/6i treatment.

Conclusions:

  • Combined MEKi and CDK4/6i treatment in uveal melanoma induces adaptive resistance through OxPhos upregulation.
  • Targeting the metabolic state of oxidative phosphorylation presents a promising strategy to enhance combination therapy efficacy in uveal melanoma.

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