Activation of WNT/β-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations.
Animals
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
/ genetics
Colorectal Neoplasms
/ genetics
Drug Resistance, Neoplasm
/ physiology
Humans
Mice
Morpholines
/ pharmacology
Mutation
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
/ pharmacology
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Triazines
/ pharmacology
Wnt Signaling Pathway
/ physiology
Xenograft Model Antitumor Assays
GSK3β
PI3K/mTOR dual inhibitor
TCF7 frameshift mutation
WNT/β-catenin signaling pathway
colorectal cancer
organoids
patient-derived colorectal cancer
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 01 2019
15 01 2019
Historique:
received:
22
11
2017
revised:
18
04
2018
accepted:
07
06
2018
pubmed:
7
7
2018
medline:
6
4
2019
entrez:
7
7
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 29978469
doi: 10.1002/ijc.31662
pmc: PMC6587482
doi:
Substances chimiques
Morpholines
0
Phosphoinositide-3 Kinase Inhibitors
0
Protein Kinase Inhibitors
0
Triazines
0
gedatolisib
96265TNH2R
MTOR protein, human
EC 2.7.1.1
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
389-401Informations de copyright
© 2018 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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