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

Xiaowei Xu, Carmine De Angelis, Kathleen A. Burke, Agostina Nardone, Huizhong Hu, Lanfang Qin, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Laura M. Heiser, Nicholas Wang, Charlotte K.Y. Ng, Edward S. Chen, Alexander Renwick, Tao Wang, Sarmistha Nanda, Martin Shea, Tamika Mitchell, Mahitha Rajendran, Ian Waters, Daniel J. ZabranskyKenneth L. Scott, Carolina Gutierrez, Chandandeep Nagi, Felipe C. Geyer, Gary C. Chamness, Ben H. Park, Chad A. Shaw, Susan G. Hilsenbeck, Mothaffar F. Rimawi, Joe W. Gray, Britta Weigelt, Jorge S. Reis-Filho, C. Kent Osborne, Rachel Schiff

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5123-5134
Number of pages12
JournalClinical Cancer Research
Issue number17
StatePublished - Sep 1 2017

ASJC Scopus subject areas

  • General Medicine


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