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PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

Zheng Zhong1,2, Sugunavathi Sepramaniam3, Xin Hui Chew3

  • 1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.

Oncogene
|August 9, 2019
PubMed

Insights

Combining PORCN inhibitors with PI3K/mTOR inhibitors shows promise for treating pancreatic cancer. This dual inhibition strategy effectively suppressed tumor growth by targeting cell proliferation and glucose metabolism in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited therapeutic options.
  • PORCN inhibitors are effective in preclinical models of Wnt-addicted cancers, including pancreatic cancer, and are in clinical trials.
  • There is a need for combination strategies to enhance the efficacy of PORCN inhibitors.

Purpose of the Study:

  • To develop drug combination strategies to improve the therapeutic efficacy of the PORCN inhibitor ETC-159.
  • To identify additional druggable vulnerabilities in Wnt-driven pancreatic cancers.

Main Methods:

  • An in vivo CRISPR loss-of-function screen was performed to identify vulnerabilities.
  • Knockout of genes regulating PI3K/mTOR signaling was assessed.
  • Combination therapy of ETC-159 with PI3K/mTOR inhibitors was evaluated in vitro and in vivo.

Main Results:

  • Key oncogenic drivers CTNNB1, KRAS, and MYC were reidentified.
  • Glucose metabolism pathway genes were important in vivo.
  • Dual inhibition of PORCN and PI3K/mTOR synergistically suppressed Wnt-driven pancreatic cancer growth in vitro and in vivo, impacting proliferation and glucose metabolism.

Conclusions:

  • Dual PORCN and PI3K/mTOR inhibition is a potential therapeutic strategy for Wnt-driven pancreatic cancers.
  • Combination therapy with ETC-159 and PI3K/mTOR inhibitors demonstrated potent anti-tumor effects in preclinical models.

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