Research ArticleCancer therapy

HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species

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Science Signaling  01 Oct 2019:
Vol. 12, Issue 601, eaay0482
DOI: 10.1126/scisignal.aay0482

New treatment for kidney cancer

People with von Hippel-Lindau syndrome, caused by loss of the namesake gene VHL, commonly develop cysts in the kidneys and are at an increased risk of developing a type of kidney cancer called clear cell renal cell carcinoma (ccRCC). Currently, drugs that inhibit the hypoxia-inducible transcription factor HIF-2α show some efficacy but only in some patients. Nicholson et al. performed a screen to identify targets that selectively limited the growth of VHL−/− fly cells. Confirmed in human ccRCC cells and patient-derived xenografts in mice, they found that inhibiting the cyclin-dependent kinases CDK4 and CDK6 together impaired tumor growth in VHL−/− ccRCC regardless of HIF-2α dependency. These findings suggest a potential and more broadly applicable therapy for ccRCC patients.

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.

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