Abstract 2654: Synergistic inhibition of cancer cell viability and suppression of HIF1α by CDK4 inhibitors and HSP90 inhibitors across cancer types

Abstract

Abstract Hypoxia is common and hypoxia-inducible factor 1α (HIF1) promotes various aspects of cancer, such as angiogenesis, or metastasis, and confers therapy resistance. Targeting HIF’s is a promising cancer treatment strategy. We previously showed that cyclin-dependent kinase 1 and 4 (CDK1, CDK4) stabilize HIF1α protein in cancer cells (Warfel et al., Cell Cycle, 2013). We also found that CDK activity facilitates HSP90 stabilization of HIF1α and that targeting CDK1 or CDK4/6 and HSP90 simultaneously reduces HIF1α levels and inhibits colorectal cancer (CRC) cell viability. The CDK4/6i palbociclib plus HSP90i ganetespib synergistically inhibit cell viability in HCT116 CRC cells under normoxia and hypoxia, show anti-tumor efficacy in vivo, and reduce both HIF1 and HIF2 levels. To investigate the translational potential of the combination strategy, we explored use of a HSP90i in clinical trials as no HSP90i has been FDA-approved for cancer treatment. Onalespib is a HSP90i undergoing phase I trials for solid tumors and lymphoma. and XL888 is being tested in GI cancer and melanoma. A third HSP90i, TAS116, is under investigation in solid tumors. We found that all these HSP90 inhibitors, in combination with palbociclib, reduce HIF1α levels in CRC cells. Cell viability was inhibited by the combination treatment in a synergistic manner. Similar effects were observed in pancreatic cancer, breast cancer and other tumor types upon treatment with TAS116 and palbociclib. As palbociclib is not the only FDA-approved CDK4/6 inhibitor, we examined the anti-tumor effects of HIF targeting effect using an alternative FDA-approved CDK4/6 inhibitor, abemaciclib. Abemaciclib, in combination with TAS116, decreased HIF1α levels and inhibited cancer cell viability. Our findings demonstrate a class effect towards HIF1α inhibition and cancer cell viability across multiple tumor types from the combination of a CDK4/6i and HSP90i. Ongoing experiments are examining the role of HIF in the sensitivity to the drug combination and the impact of the combined inhibitor therapy on cancer cell migration and invasion. Further clinical translation of this concept is warranted for cancer therapy. Citation Format: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry. Synergistic inhibition of cancer cell viability and suppression of HIF1α by CDK4 inhibitors and HSP90 inhibitors across cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2654.