Radiosensitization of the PI3K inhibitor HS-173 through reduction of DNA damage repair in pancreatic cancer

Abstract

Activation of PI3K/AKT pathway occurs frequently in tumors and is correlated with radioresistance. The PI3K/AKT pathway can be an important target for improvement of radiotherapy. Although adding of chemotherapy to radiation therapy regimen enhances survival in patients with locally advanced pancreatic cancer, more effective therapies for increasing radiosensitivity are urgently needed. In this study, we investigated whether the novel PI3K inhibitor HS-173 could attenuate radiation-induced up-regulation of DNA damage repair processes and assessed its efficacy as a radio- and chemo-sensitizer. Radiosensitizing effects of HS-173 were tested in human pancreatic cells using clonogenic survival and growth assays. Mechanisms underlying the effects of HS-173 and radiation were determined by assessing cell cycle and DNA damage- repair pathway components, including ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The in vivo efficacy of HS-173 in cancer radiotherapy was evaluated using a human tumor xenograft model. HS-173 significantly increased the sensitivity of pancreatic cancer cells to radiation, an effect that was associated with G2/M cell cycle arrest. HS-173 also significantly attenuated DNA damage repair by potently inhibiting ATM and DNA-PKcs, the two major kinases that respond to radiation-induced DNA double-strand breaks (DSBs), resulting in sustained DNA damage. Moreover, the combination of HS-173 and radiation delayed tumor growth and impaired DNA repair in a pancreatic cancer xenograft model, reflecting enhanced radiosensitization. These results showed that HS-173 significantly improved radiotherapy by inhibiting the DNA damage-repair pathway in pancreatic cancer. We therefore suggest that HS-173 may be an effective radiosensitizer for pancreatic cancer.