Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4.
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.
School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Susan
S
Breslin
School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Michelle C
MC
Lowry
School of Pharmacy and Pharmaceutical Sciences and Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Lorraine
L
O'Driscoll
D000077716:Afatinib; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077341:Lapatinib; D011799:Quinazolines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology; D015854:Up-Regulation
D000077716:Afatinib; D051544:Cytochrome P-450 CYP3A; D000077341:Lapatinib; D011799:Quinazolines; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C510163:CYP3A4 protein, human; C508053:ERBB2 protein, human; C487932:neratinib