Abstract 5816: Inhibition of Hsp90 sensitizes pancreatic cancer in vitro and in vivo to chemo-radiotherapy

Purpose: Important signaling pathways contributing to proliferation, development, metastasis and resistance to chemo-radiotherapy in pancreatic adenocarcinoma (PDAC) includes the PI3K/AKT/HIF-1α/STAT-3 pathway. The molecular chaperone heat shock protein 90 (HSP90) controls the activity, stability, turnover, and trafficking of many molecules involved in these major signaling pathways. Functional inhibition of HSP90 may inhibit these pathways simultaneously. We evaluated the efficacy of HSP90 functional inhibitor ganetespib in combination with chemo-radiotherapy against PDAC in vitro and in vivo.

Methods and Materials: Cell proliferation (Br-dU), colony formation (clonogenic assay), migration (spheroid), and Western blot analyses were carried out in HPAC and PANC-1 PDAC cell lines to determine the effect of ganetespib alone or in combination with 5-FU+ 2Gy XRT. Tumor regression study of PDAC with ganetespib alone and in combination with chemo-radiation was analyzed in xenograft mouse models.

Results: At the clinically achievable dose of 50 nM, ganetespib inhibited PDAC cells proliferation (p<0.001), potentiated 5-FU chemotherapy and 2Gy of ionizing radiation (p<0.001), and decreased the levels of survival molecules such as PI3K, p-AKT, and p-ERK in vitro. Additionally, ganetespib indeed potentiates the effects of chemo-radiation in both cell lines: significant decrease in colony formation as well as decrease in migration. Combinations of ganetespib and chemo-radiation therapy demonstrated synergistic ability in human xenograft mouse models (p<0.001).

Conclusion: Ganetespib potentiates the effects of chemo-radiation in preclinical studies. Evaluating HSP90 inhibitors in PDAC patients is a rational approach in assessing the fatal PDAC.

Citation Format: Ganji Purnachandra Nagaraju, Bassel F. El-Rayes. Inhibition of Hsp90 sensitizes pancreatic cancer in vitro and in vivo to chemo-radiotherapy [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 5816.