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Published on: May 27, 2021
HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species
Hilary E Nicholson1, Zeshan Tariq1, Benjamin E Housden2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Abstract:
Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and Drosophila) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2α was not required for the increased CDK4/6 requirement of VHL ccRCC cells. Accordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent VHL ccRCC cells and not antagonistic with HIF-2α inhibition in HIF-2α-independent cells. These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in combination with HIF-2α inhibitors.
Insights
Clear cell renal cell carcinoma (ccRCC) cells with VHL inactivation exhibit synthetic lethality with CDK4/6 inhibition. Combining CDK4/6 and HIF-2α inhibitors may improve ccRCC treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (ccRCC) initiation involves VHL tumor suppressor gene inactivation, leading to hypoxia-inducible factor 2α (HIF-2α) accumulation.
- While HIF-2α inhibitors show efficacy, resistance mechanisms necessitate alternative therapeutic strategies for ccRCC.
Purpose of the Study:
- To investigate the synthetic lethality between VHL inactivation and cyclin-dependent kinases 4 and 6 (CDK4/6) activity in ccRCC.
- To evaluate the synergistic effects of combining CDK4/6 and HIF-2α inhibitors in ccRCC models.
Main Methods:
- Utilized human and Drosophila models, ccRCC cell lines, and xenografts to study VHL inactivation and CDK4/6 activity.
- Assessed the impact of HIF-2α on CDK4/6-cyclin D1 pathway and the antiproliferative effects of combined inhibitions.
Main Results:
- Identified synthetic lethality between decreased CDK4/6 activity and VHL inactivation across species and ccRCC models.
- Demonstrated synergistic antiproliferative effects of combined CDK4/6 and HIF-2α inhibition in HIF-2α-dependent ccRCC cells.
Conclusions:
- CDK4/6 inhibition presents a potential therapeutic strategy for ccRCC, particularly in combination with HIF-2α inhibitors.
- Findings support clinical trials testing CDK4/6 inhibitors, alone or combined with HIF-2α inhibitors, for ccRCC treatment.
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