PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers.
Adult
Afatinib
/ pharmacology
Aged
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
/ biosynthesis
Class Ia Phosphatidylinositol 3-Kinase
Drug Resistance, Neoplasm
/ genetics
Female
Genital Neoplasms, Female
/ drug therapy
Humans
Mice
Mice, SCID
Middle Aged
Mutation
Phosphatidylinositol 3-Kinases
/ biosynthesis
Protein Kinase Inhibitors
/ pharmacology
Receptor, ErbB-2
/ biosynthesis
Transfection
Xenograft Model Antitumor Assays
Afatinib
Gynecological cancer
HER2/neu overexpression
Mechanism of resistance
PI3K mutation
Journal
Gynecologic oncology
ISSN: 1095-6859
Titre abrégé: Gynecol Oncol
Pays: United States
ID NLM: 0365304
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
08
11
2018
revised:
21
12
2018
accepted:
02
01
2019
pubmed:
12
1
2019
medline:
14
5
2019
entrez:
12
1
2019
Statut:
ppublish
Résumé
Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu. We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting. We found PI3K wild-type cell-lines to be significantly more sensitive (lower IC Oncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.
Identifiants
pubmed: 30630630
pii: S0090-8258(19)30004-6
doi: 10.1016/j.ygyno.2019.01.002
pmc: PMC6430698
mid: NIHMS1518190
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
Afatinib
41UD74L59M
PIK3R1 protein, human
EC 2.7.1.-
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
Class Ia Phosphatidylinositol 3-Kinase
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
ERBB2 protein, human
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
158-164Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016359
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA176067
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
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