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

Oncogene
Zheng ZhongDavid M Virshup

Abstract

Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is aggressive and lethal. Although there is an urgent need for effective therapeutics in treating pancreatic cancer, none of the targeted therapies tested in clinical trials to date significantly improve its outcome. PORCN inhibitors show efficacy in preclinical models of Wnt-addicted cancers, including RNF43-mutant pancreatic cancers and have advanced to clinical trials. In this study, we aimed to develop drug combination strategies to further enhance the therapeutic efficacy of the PORCN inhibitor ETC-159. To identify additional druggable vulnerabilities in Wnt-driven pancreatic cancers, we performed an in vivo CRISPR loss-of-function screen. CTNNB1, KRAS, and MYC were reidentified as key oncogenic drivers. Notably, glucose metabolism pathway genes were important in vivo but less so in vitro. Knockout of multiple genes regulating PI3K/mTOR signaling impacted the growth of Wnt-driven pancreatic cancer cells in vivo. Importantly, multiple PI3K/mTOR pathway inhibitors in combination with ETC-159 synergistically suppressed the growth of multiple Wnt-addicted cancer cell lines in soft agar. Furthermore, the combination of the PORCN inhibitor ETC-159 and the pan-PI3K inhibi...Continue Reading

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Methods Mentioned

BETA
gene knockout
xenograft
xenografts
transfection
PCR

Clinical Trials Mentioned

NCT01351103
NCT02278133
NCT02521844
NCT03447470
NCT02675946
NCT03507998

Software Mentioned

edgeR
processAmplicons
Chou
Talalay CompuSyn
MAGeCK
GraphPad Prism
Chou CompuSyn software
R

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