HIF1α inhibition by dual targeting of CDK4/6 and HSP90 reduces cancer cell viability including Rb-deficient cells

Most cancers harbor intra-tumoral hypoxia which promotes tumor progression and therapy resistance. Hypoxia-inducible factor 1α (HIF1α) mediates an adaptive response to hypoxia and contributes to multiple cancer hallmarks. We describe cancer therapeutic targeting of HIF1α by combination of CDK4/6 inhibitors (CDK4/6i) and heat-shock protein 90 inhibitors (HSP90i). CDK1 contributes to HSP90-mediated HIF1α stabilization whereas CDK1-knockdown enhances HIF1α reduction by HSP90i. Dual CDK1- and HSP90-inhibition increases apoptosis and synergistically inhibits cancer cell viability. To translate our findings, we use FDA-approved CDK4/6i in combination with HSP90i to reduce HIF1α expression and suppress viability of multiple cancer cell types, including Rb-deficient cancer cells. Overexpression of HIF1α668E partially rescues the cell viability inhibition by combination CDK4/6i and HSP90i treatment under hypoxia. CDK4/6i and HSP90i suppresses tumor growth in vivo . Thus, combined targeting of CDK4/6 and HSP90, through a drug class effect, inhibits HIF1α and shows preclinical anti-cancer therapeutic efficacy, including with Rb-deficiency. ### Competing Interest Statement The authors have declared no competing interest.