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

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.

Pharmacologic profiling reveals lapatinib as a novel antiviral against SARS-CoV-2 in vitro

“…These multiple concentrations provided a broad picture of each drugs’ ability to block virus-induced CPE. For our screen, we repurposed a drug library that focused on cancer and metabolic targets, which previously had been used to examined drug sensitivities in cancer cells (Harris et al, 2019; Nicholson et al, 2019; Shu et al, 2020). The maximal inhibition of viral killing in cells (at any dose) was used to identify compounds as potential hits (Fig.…”

“…This enabled us to identify concentrations of compounds that inhibit virally-induced killing while also maintaining cell viability. Similar drug screening approaches have successfully identified selective vulnerabilities in cancer cells (Harris et al, 2019; Nicholson et al, 2019; Shu et al, 2020). To facilitate rapid screening, we tested the minimally pathogenic human coronavirus, OC43, which belongs to the same betacoronavirus genus as SARS-CoV-2.…”

The m 6 A RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor

“…Traditionally, candidate synthetic lethal (SL) partners have been identified through large-scale functional screens in cell lines using shRNA, CRISPR, or small molecule libraries. Using these approaches, a number of VHL SL interactions have been identified (19)(20)(21)(22)(23)(24). More recently, computational methods have been utilized to predict SL partners of somatic mutations in human cancer using genomic data sets (25,26).…”

Targeting the Deterministic Evolutionary Trajectories of Clear Cell Renal Cell Carcinoma

“…It is worth noting that the aforementioned drugs are directed against downstream effectors of VHL, hence, from an evolutionary point of view, there is a potential to better define the molecular target. Nicholson et al found that inhibiting the cyclin-dependent kinases CDK4 and CDK6 impaired tumor growth in VHL-deficient ccRCC regardless of HIF2α dependency [40]. Abemaciclib, a CDK4/6 and PIM1 kinase inhibitor is currently being tested in phase I trial in combination with sunitinib in metastatic RCC (NCT03905889).…”