Neratinib-resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4
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Journal ArticleDate:
2017Access:
openAccessCitation:
Breslin, S., Lowry, M. & O'Driscoll, L., Neratinib-resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4, British Journal of Cancer, 116, 5, 2017, 620 - 625Abstract:
Background:
Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance.
Methods:
Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to neratinib was assessed. Cellular phenotype changes were evaluated using migration, invasion and anoikis assays. Immunoblotting for HER family members and drug efflux pumps, as well as enzyme activity assays were performed.
Results:
Neratinib resistance conferred cross-resistance to trastuzumab, lapatinib and afatinib. Furthermore, the efficacy of neratinib was reduced in trastuzumab- and lapatinib-resistant cells. Neratinib-resistant cells were more aggressive than their drug-sensitive counterparts, with increased CYP3A4 activity identified as a novel mechanism of neratinib resistance.
Conclusions:
The potential of increased CYP3A4 activity as a biomarker and/or target to add value to neratinib warrants investigation.
Sponsor
Grant Number
Irish Cancer Society
CCRC13GAL
Trinity Foundation
Author's Homepage:
http://people.tcd.ie/lodriscDescription:
PUBLISHEDSponsor:
Irish Cancer SocietyTrinity Foundation
Type of material:
Journal ArticleSeries/Report no:
British Journal of Cancer;116;
5;
Availability:
Full text availableSubject (TCD):
Cancer , CANCER , DRUG RESISTANCEDOI:
10.1038/bjc.2016.445Metadata
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