Open Access

ARTICLE

mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

by CHIWEN BU^1,2, LIGANG ZHAO¹, LISHAN WANG¹, ZEQIAN YU¹, JIAHUA ZHOU^1,*

1 Department of Hepatobiliary and Pancreatic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
2 School of Medicine, Southeast University, Nanjing, 210009, China

* Corresponding Author: JIAHUA ZHOU. Email:

Oncology Research 2023, 31(4), 495-503. https://doi.org/10.32604/or.2023.029309

Received 12 February 2023; Accepted 17 April 2023; Issue published 25 June 2023

Abstract

Pancreatic cancer is one of the most aggressive cancers with a median survival time of less than 5 months, and conventional chemotherapeutics are the main treatment strategy. Poly(ADP-ribose) polymerase (PARP) inhibitors have been recently approved for BRCA1/2-mutant pancreatic cancer, opening a new era for targeted therapy for this disease. However, most pancreatic cancer patients carry wild-type BRCA1/2 with resistance to PARP inhibitors. Here, we reported that mammalian target of rapamycin complex 2 (mTORC2) kinase is overexpressed in pancreatic cancer tissues and promotes pancreatic cancer cell growth and invasion. Moreover, we found that knockdown of the mTORC2 obligate subunit Rictor sensitized pancreatic cancer cells to the PARP inhibitor olaparib. Mechanistically, we showed that mTORC2 positively regulates homologous recombination (HR) repair by modulating BRCA1 recruitment to DNA double-strand breaks (DSBs). In addition, we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the PARP inhibitor olaparib synergistically inhibited pancreatic cancer growth in vivo. Thus, this study provides a novel target and strategy for optimizing PARP inhibitor efficiency in pancreatic cancers.

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