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Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism

Jordan M Thompson1, Alejandro Alvarez1, Monika K Singha1

  • 1Molecular Biology and Biochemistry Department, University of California Irvine, Irvine, California.

Molecular Cancer Therapeutics
|May 4, 2018
PubMed

Insights

Statins, HMG-CoA reductase inhibitors, show promise as a new treatment for clear cell renal cell carcinoma (CC-RCC). They are synthetically lethal with von Hippel-Lindau (VHL) gene loss, a common CC-RCC driver.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Clear cell renal cell carcinoma (CC-RCC) presents limited treatment options for advanced stages.
  • The von Hippel-Lindau (VHL) tumor suppressor gene is lost in 90% of CC-RCC cases, driving disease progression.

Purpose of the Study:

  • To investigate HMG-CoA reductase inhibitors (statins) as potential therapeutics for CC-RCC.
  • To explore the synthetic lethality between statins and VHL gene loss in CC-RCC.

Main Methods:

  • Utilized three different CC-RCC cell lines and three lipophilic statins.
  • Assessed the impact of statin treatment on VHL-deficient CC-RCC cell viability and tumor growth in mice.
  • Investigated the rescue mechanisms of the synthetic lethal effect using mevalonate, geranylgeranylpyrophosphate, and squalene.

Main Results:

  • Statin treatment demonstrated synthetic lethality with VHL loss in CC-RCC.
  • Statins induced cytostatic and cytotoxic effects in VHL-deficient CC-RCC cells at nanomolar and micromolar concentrations, respectively.
  • The synthetic lethality was attributed to the disruption of small GTPase isoprenylation, involving Rho/ROCK and HIF signaling pathways.
  • Statin treatment inhibited tumor initiation and progression in a mouse model of CC-RCC.

Conclusions:

  • Statins represent a potential therapeutic strategy for VHL-deficient CC-RCC.
  • Targeting mevalonate synthesis and subsequent isoprenylation is a promising approach for CC-RCC treatment.

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