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mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

Chiwen Bu1,2, Ligang Zhao1, Lishan Wang1

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

Oncology Research
|July 7, 2023
PubMed

Insights

Targeting mTORC2 enhances PARP inhibitor effectiveness in pancreatic cancer. This study reveals mTORC2 promotes cancer growth and resistance, offering a new strategy for treating patients with wild-type BRCA1/2 mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Pancreatic cancer has a poor prognosis, with limited treatment options beyond conventional chemotherapy.
  • Poly(ADP-ribose) polymerase (PARP) inhibitors offer targeted therapy for BRCA1/2-mutant pancreatic cancer, but most patients have wild-type BRCA1/2 and are resistant.
  • Mammalian target of rapamycin complex 2 (mTORC2) is implicated in cancer progression.

Purpose of the Study:

  • To investigate the role of mTORC2 in pancreatic cancer growth and its potential as a therapeutic target.
  • To determine if targeting mTORC2 can overcome resistance to PARP inhibitors in pancreatic cancer.
  • To elucidate the mechanism by which mTORC2 influences DNA repair pathways.

Main Methods:

  • Overexpression of mTORC2 in pancreatic cancer tissues was analyzed.
  • Knockdown of Rictor, an mTORC2 subunit, was performed to assess sensitivity to olaparib.
  • Homologous recombination (HR) repair mechanisms, including BRCA1 recruitment to DNA double-strand breaks (DSBs), were studied.
  • Combination therapy with an mTORC2 inhibitor (PP242) and olaparib was evaluated in vivo.

Main Results:

  • mTORC2 is overexpressed in pancreatic cancer and promotes cell growth and invasion.
  • Rictor knockdown sensitized pancreatic cancer cells to the PARP inhibitor olaparib.
  • mTORC2 positively regulates HR repair by affecting BRCA1 recruitment to DSBs.
  • Combined treatment with PP242 and olaparib synergistically inhibited tumor growth in vivo.

Conclusions:

  • mTORC2 is a key regulator of homologous recombination repair in pancreatic cancer.
  • Targeting mTORC2 represents a novel strategy to enhance the efficacy of PARP inhibitors in pancreatic cancer, particularly in patients with wild-type BRCA1/2.
  • This research provides a promising therapeutic approach for a broader range of pancreatic cancer patients.
Keywords:
DNA damageHR repairPARP inhibitorsPancreatic cancermTORC2

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