Format

Send to

Choose Destination
Int J Cancer. 2019 Jan 15;144(2):389-401. doi: 10.1002/ijc.31662. Epub 2018 Nov 29.

Activation of WNT/β-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations.

Park YL1,2, Kim HP1,2, Cho YW1,2, Min DW1,2, Cheon SK1,2, Lim YJ3, Song SH2, Kim SJ4, Han SW2,3, Park KJ5, Kim TY1,2,3.

Author information

1
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
2
Cancer Research Institute, Seoul National University, Seoul, South Korea.
3
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
4
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA.
5
Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.

Abstract

PIK3CA is a frequently mutated gene in cancer, including about ~15 to 20% of colorectal cancers (CRC). PIK3CA mutations lead to activation of the PI3K/AKT/mTOR signaling pathway, which plays pivotal roles in tumorigenesis. Here, we investigated the mechanism of resistance of PIK3CA-mutant CRC cell lines to gedatolisib, a dual PI3K/mTOR inhibitor. Out of a panel of 29 CRC cell lines, we identified 7 harboring one or more PIK3CA mutations; of these, 5 and 2 were found to be sensitive and resistant to gedatolisib, respectively. Both of the gedatolisib-resistant cell lines expressed high levels of active glycogen synthase kinase 3-beta (GSK3β) and harbored the same frameshift mutation (c.465_466insC; H155fs*) in TCF7, which encodes a positive transcriptional regulator of the WNT/β-catenin signaling pathway. Inhibition of GSK3β activity in gedatolisib-resistant cells by siRNA-mediated knockdown or treatment with a GSK3β-specific inhibitor effectively reduced the activity of molecules downstream of mTOR and also decreased signaling through the WNT/β-catenin pathway. Notably, GSK3β inhibition rendered the resistant cell lines sensitive to gedatolisib cytotoxicity, both in vitro and in a mouse xenograft model. Taken together, these data demonstrate that aberrant regulation of WNT/β-catenin signaling and active GSK3β induced by the TCF7 frameshift mutation cause resistance to the dual PI3K/mTOR inhibitor gedatolisib. Cotreatment with GSK3β inhibitors may be a strategy to overcome the resistance of PIK3CA- and TCF7-mutant CRC to PI3K/mTOR-targeted therapies.

KEYWORDS:

GSK3β; PI3K/mTOR dual inhibitor; TCF7 frameshift mutation; WNT/β-catenin signaling pathway; colorectal cancer; organoids; patient-derived colorectal cancer

PMID:
29978469
DOI:
10.1002/ijc.31662
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center