Abstract PD2-05: Inhibition of mutant HER2 results in synthetic lethality when combined with ER antagonists in ER+/HER2 mutant human breast cancer cells

摘要: Background: Human epidermal growth factor receptor 2 (ERBB2 or commonly known as HER2) missense mutations have been reported in 2-4% of breast cancers and occur primarily the absence HER2 gene amplification. Based on TCGA, approximately 60% these tumors are hormone-dependent express estrogen (ER) a. Among ER+ with mutations, more than 80% kinase domain. We examined herein whether ER+/HER2 mutant cancer cells resistant to anti-estrogen therapies and, thus, they should be treated combined ER inhibitors. Methods: Three common activating (G309A, L755S, V777L) wild type (WT) were incorporated into MCF7 using AAV-mediated homologous recombination. The isogenic incorporation a heterozygous mutation accurately represents primary human compared transfection overexpression exogenous vectors. cell viability transcriptional activity, an ERE-luciferase reporter, response deprivation treatment fulvestrant (a selective downregulator) neratinib (an irreversible, pan-HER tyrosine inhibitor), either alone combination. Signaling downstream was by immunoblot analysis. In vivo anti-tumor efficacy ± is currently being assessed ovariectomized athymic mice bearing MCF7/HER2V777L xenografts. Results: containing (L755S V777L), but not HER2WT extracellular domain (G309A), able proliferate exponentially estrogen-free medium. MCF7/HER2L755S also 1 mM fulvestrant, despite fulvestrant9s ability downregulate cells. Additionally, showed increased levels pERK p70S6K. Treatment 200 nM potently inhibited conditions resensitized them while partially downregulating levels. Addition estradiol markedly rescued all three from neratinib-induced death suggesting that inhibition both required for tumor apoptosis. Using ERE-luc reporter assays, did inhibit basal estrogen-induced activity ERα Ser118 phosphorylation, thus supporting mutation-to-ER crosstalk genetically engineered This result suggests pathways can operate independently it dual pathway results synthetic lethality. Conclusions: These data suggest that, similar amplification, induce resistance antiestrogen therapies. Therefore, we propose simultaneous therapeutic targeting signaling maximal harboring investigated phase II SUMMIT trial (NCT01953926). Citation Format: Croessmann S, Zabransky DJ, Cutler, Jr. RE, Lalani AS, Park BH, Arteaga CL. Inhibition lethality when antagonists [abstract]. In: Proceedings 2016 San Antonio Breast Cancer Symposium; Dec 6-10; Antonio, TX. Philadelphia (PA): AACR; Res 2017;77(4 Suppl):Abstract nr PD2-05.