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Requirement for Cyclin D1 Underlies Cell-Autonomous HIF2 Dependence in Kidney Cancer

Nitin H Shirole1,2, Devishi Kesar2, Yenarae Lee2

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Cancer Discovery
|April 3, 2025
PubMed

Insights

Sustaining Cyclin D1 expression confers resistance to belzutifan, a treatment for clear cell renal carcinoma (ccRCC). This resistance involves both kinase-dependent and independent activities of Cyclin D1.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Clear cell renal carcinoma (ccRCC) is driven by HIF2a stabilization due to VHL gene inactivation.
  • Belzutifan, a HIF2a inhibitor, treats ccRCC but faces challenges with de novo and acquired resistance.
  • HIF2a, complexed with ARNT, regulates gene transcription crucial for ccRCC progression.

Purpose of the Study:

  • To identify HIF2a-responsive genes conferring resistance to belzutifan in ccRCC.
  • To elucidate the mechanisms by which CCND1 (Cyclin D1) promotes resistance.
  • To investigate the roles of Cdk4/6, pRB, and its paralogs in Cyclin D1-mediated resistance.

Main Methods:

  • CRISPR activation (CRISPRa) screens in ccRCC cell lines resistant to a belzutifan analog.
  • Analysis of CCND1 expression and its impact on HIF2a-dependency.
  • Assessment of Cyclin D1's role in resistance using wild-type and kinase-defective variants, and cell lines with depleted pRB family members.

Main Results:

  • Sustained expression of the HIF2a target gene CCND1 confers HIF2a-independence and belzutifan resistance.
  • Cyclin D1's resistance-promoting activity requires Cdk4/6 activation but extends beyond pRB phosphorylation.
  • A kinase-defective Cyclin D1 variant partially overcame belzutifan's effects, indicating kinase-independent roles.

Conclusions:

  • CCND1 is a key mediator of belzutifan resistance in ccRCC.
  • Cyclin D1 promotes ccRCC growth through both Cdk4/6-dependent phosphorylation of pRB paralogs and kinase-independent mechanisms.
  • Targeting CCND1 or its associated pathways may overcome belzutifan resistance in ccRCC.

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