HER2 reactivation through acquisition of the HER2 L755S mutation as a mechanism of acquired resistance to HER2-targeted therapy in HER2(+) breast cancer Journal Article

   

Authors:	Xu, X.; De Angelis, C.; Burke, K. A.; Nardone, A.; Hu, H.; Qin, L.; Veeraraghavan, J.; Sethunath, V.; Heiser, L. M.; Wang, N.; Ng, C. K. Y.; Chen, E. S.; Renwick, A.; Wang, T.; Nanda, S.; Shea, M.; Mitchell, T.; Rajendran, M.; Waters, I.; Zabransky, D. J.; Scott, K. L.; Gutierrez, C.; Nagi, C.; Geyer, F. C.; Chamness, G. C.; Park, B. H.; Shaw, C. A.; Hilsenbeck, S. G.; Rimawi, M. F.; Gray, J. W.; Weigelt, B.; Reis-Filho, J. S.; Osborne, C. K.; Schiff, R.
Article Title:	HER2 reactivation through acquisition of the HER2 L755S mutation as a mechanism of acquired resistance to HER2-targeted therapy in HER2(+) breast cancer
Abstract:	Purpose: Resistance to anti-HER2 therapies in HER2+ breast cancer can occur through activation of alternative survival pathways or reactivation of the HER signaling network. Here we employed BT474 parental and treatment-resistant cell line models to investigate a mechanism by which HER2+ breast cancer can reactivate the HER network under potent HER2-targeted therapies. Experimental Design: Resistant derivatives to lapatinib (L), trastuzumab (T), or the combination (LR/TR/LTR) were developed independently from two independent estrogen receptor ER+/HER2+ BT474 cell lines (AZ/ATCC). Two derivatives resistant to the lapatinib-containing regimens (BT474/AZ-LR and BT474/ATCC-LTR lines) that showed HER2 reactivation at the time of resistance were subjected to massive parallel sequencing and compared with parental lines. Ectopic expression and mutant-specific siRNA interference were applied to analyze the mutation functionally. In vitro and in vivo experiments were performed to test alternative therapies for mutant HER2 inhibition. Results: Genomic analyses revealed that the HER2L755S mutation was the only common somatic mutation gained in the BT474/AZ-LR and BT474/ATCC-LTR lines. Ectopic expression of HER2L755S induced acquired lapatinib resistance in the BT474/AZ, SK-BR-3, and AU565 parental cell lines. HER2L755S-specific siRNA knockdown reversed the resistance in BT474/AZ-LR and BT474/ATCC-LTR lines. The HER1/2irreversible inhibitors afatinib and neratinib substantially inhibited both resistant cell growth and the HER2 and downstream AKT/MAPK signaling driven by HER2L755S in vitro and in vivo. Conclusions: HER2 reactivation through acquisition of the HER2L755S mutation was identified as a mechanism of acquired resistance to lapatinib-containing HER2-targeted therapy in preclinical HER2-amplified breast cancer models, which can be overcome by irreversible HER1/2 inhibitors. © 2017 American Association for Cancer Research.
Journal Title:	Clinical Cancer Research
Volume:	23
Issue:	17
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2017-09-01
Start Page:	5123
End Page:	5134
Language:	English
DOI:	10.1158/1078-0432.ccr-16-2191
PROVIDER:	scopus
PUBMED:	28487443
PMCID:	PMC5762201
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85029527180&doi=10.1158%2f1078-0432.CCR-16-2191&partnerID=40&md5=7a2f57cb01231e79903e881869fd6797
Notes:	Article -- Export Date: 2 October 2017 -- Source: Scopus

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