1区 · 医学
Article
作者: Zabransky, Daniel J. ; Burke, Kathleen A. ; Qin, Lanfang ; Geyer, Felipe C. ; Reis-Filho, Jorge S. ; Rimawi, Mothaffar F. ; Shaw, Chad A. ; Renwick, Alexander ; Rajendran, Mahitha ; Nagi, Chandandeep ; Chamness, Gary C. ; Scott, Kenneth L. ; Shea, Martin ; Gutierrez, Carolina ; Wang, Tao ; Chen, Edward S. ; Schiff, Rachel ; Veeraraghavan, Jamunarani ; Hilsenbeck, Susan G. ; Gray, Joe W. ; Hu, Huizhong ; Park, Ben H. ; Nardone, Agostina ; De Angelis, Carmine ; Ng, Charlotte K.Y. ; Xu, Xiaowei ; Wang, Nicholas ; Heiser, Laura M. ; Weigelt, Britta ; Nanda, Sarmistha ; Mitchell, Tamika ; Osborne, C. Kent ; Sethunath, Vidyalakshmi ; Waters, Ian
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 HER1/2–irreversible 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. Clin Cancer Res; 23(17); 5123–34. ©2017 AACR.