Different mechanisms for resistance to trastuzumab versus lapatinib in her2- positive breast cancers - role of estrogen receptor and her2 reactivation
Wang, Yen-Chao Morrison, Gladys Gillihan, Ryan Guo, Jun Ward, Robin M Fu, Xiaoyong Botero, Maria F Healy, Nuala A Hilsenbeck, Susan G Phillips, Gail Lewis
Wang, Yen-Chao
Morrison, Gladys
Gillihan, Ryan
Guo, Jun
Ward, Robin M
Fu, Xiaoyong
Botero, Maria F
Healy, Nuala A
Hilsenbeck, Susan G
Phillips, Gail Lewis
Publication Date
2011-11-28
Type
Article
Downloads
Citation
Wang, Yen-Chao; Morrison, Gladys; Gillihan, Ryan; Guo, Jun; Ward, Robin M; Fu, Xiaoyong; Botero, Maria F; Healy, Nuala A; Hilsenbeck, Susan G; Phillips, Gail Lewis; Chamness, Gary C; Rimawi, Mothaffar F; Osborne, C Kent; Schiff, Rachel (2011). Different mechanisms for resistance to trastuzumab versus lapatinib in her2- positive breast cancers - role of estrogen receptor and her2 reactivation. Breast Cancer Research 13 (6),
Abstract
Introduction: The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs. Methods: Response to L + T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and estrogen receptor (ER) pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L + T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts. Results: ER or its downstream products increased in four out of the five ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was up-regulated and promoted survival via various Bcl2 family members. These L-and L + T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L + T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3, and receptor ligands) to overcome L's effects. The combination of endocrine and L + T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts. Conclusions: Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients.
Funder
Publisher
Springer Nature
Publisher DOI
Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland