Abstract 2798: Enhanced HIF1α inhibition through dual inhibition of CDK and HSP90

Abstract

Abstract A prevalent characteristic of solid tumors is the presence of hypoxic areas. Intratumoral hypoxia plays a well-known role in chemotherapy and radiotherapy resistance and is associated with poor prognosis as well as enhanced metastasis. Hypoxia-inducible factor 1α (HIF1α) is a major mediator of the cellular response to hypoxia, which promotes malignant proliferation and progression in cancers. HIF-1α expression is increased in a variety of tumors but this is not restricted to hypoxic regions. Understanding and targeting the mechanism of cancer-related HIF1α stabilization may help to improve current cancer treatments. 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 manner both under hypoxia and at G2/M under normoxia (Warfel et al., Cell Cycle, 2013). Another previously acknowledged VHL-independent HIF1α stabilizer is the heat shock protein 90 (HSP90) that has been correlated with adverse prognosis and used as a therapeutic target in cancer. We investigated potential crosstalk between CDK1-mediated and HSP90-mediated HIF1α stabilization and the potential for therapeutic targeting. We found that under hypoxia, the interaction between HSP90 and HIF1α proteins is impaired by CDK1 inhibition in HCT116 colon cancer cells. Moreover, the level of HIF1α protein is increased by heat shock (40°C) treatment (as compared to 37°C), which can be reversed by the treatment with the HSP90 inhibitor, geldanamycin. Interestingly, administration of the CDK1 inhibitor, Ro-3306, is also able to decrease heat shock-induced HIF1α. Our results suggest that CDK1 activity may contribute to HSP90-mediated HIF1α stabilization. On the other hand, HIF1α level is decreased by HSP90 inhibition under hypoxia, which can be further reduced by the combination of HSP90 inhibition and CDK1 inhibition or knockdown. The joint inhibitory effect of CDK1 and HSP90 is observed in other cancer cell lines. In addition, we evaluated the combinational treatment of CDK4/HSP90 inhibition and found it robustly suppresses HIF1α expression in glioblastoma cell lines (i.e. T98G and SNB19). Ongoing studies are examining the biological function of CDK/HSP90 dual inhibition on cancer cell invasiveness as well as effects on cell viability. Our findings provide a rationale for targeting HIF1α through a novel combination of CDK and HSP90 inhibitors, a therapeutic strategy with clinical implications. Citation Format: Shuai Zhao, David T. Dicker, Wafik S. El-Deiry. Enhanced HIF1α inhibition through dual inhibition of CDK and HSP90. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2798.