Abstract 2436: Anti-cancer effect by combination treatment of CDK and HSP90 inhibitors through HIF1α inhibition

Hypoxia-inducible factor 1α (HIF1α) is the main mediator of the adaptive response to intra-tumoral hypoxia. HIF1α overexpression contributes to tumor angiogenesis, cancer cell survival and metastasis. Thus, targeting HIF1α provides new opportunities for cancer therapy. We have previously shown that cyclin-dependent kinase 1 (CDK1) stabilizes HIF1α through direct phosphorylation of its Ser668 residue in a Von Hippel-Lindau (VHL)-independent or p53-independent manner both under hypoxia and at G2/M under normoxia (Warfel et al., Cell Cycle, 2013). Because heat shock protein 90 (HSP90) is a VHL-independent HIF1α stabilizer, we hypothesized CDK and CDK inhibitor effects in the stabilization/destabilization mechanism. We found that CDK1 inhibition disrupts the interaction between HSP90 and HIF1α. Moreover, administration of the CDK1 inhibitor, Ro-3306, partially reversed a heat shock (40°C) response dependent increase in the level of HIF1α, which suggests that CDK1 activity may contribute to HSP90-mediated HIF1α stabilization. Combination treatment with both HSP90 inhibitor and CDK1 inhibition/knockdown decreased HIF1α level more robustly than either single treatment. Dual inhibition of CDK1 and HSP90 not only synergistically decreased cell viability but also remarkably reduced colony formation of HCT116 colon cancer cells. Previously we have also shown that similar to CDK1, CDK4 plays a role in HIF1α stabilization as well. This led us to investigate the effect of CDK4/HSP90 dual inhibition on colorectal cancer cells. The combination treatment of CDK4 knockdown/inhibition and HSP90 inhibition reduced the level of HIF1α in various cancer cell lines (e.g., colorectal, glioblastoma, prostate cancers). The FDA-approved CDK4 inhibitor palbociclib along with ganetespib synergistically inhibited cell viability in SW480 colon cancer cells under hypoxia or normoxia. No reduction in cell viability was noted in WI38 normal cells under normoxia at similar concentrations. In addition, we tested the therapeutic potential of the dual CDKi/HSP90i therapy in vivo. The combination treatment of palbociclib and ganetespib inhibited tumor growth in the HT29 colon cancer cell xenograft mouse model at relatively low doses. Immunohistochemistry staining of the tumor samples revealed higher levels of apoptosis, lower levels of VEGF expression and reduced microvessel formation in the combination treatment group. Our findings provide a compelling rationale for a therapeutic strategy to target HIF1α through the combination of CDK and HSP90 inhibitors in cancer therapy.

Citation Format: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry. Anti-cancer effect by combination treatment of CDK and HSP90 inhibitors through HIF1α inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2436.