Neratinib induces estrogen receptor function and sensitizes HER2-mutant breast cancer to anti-endocrine therapy

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S125-S125
• Main Authors: Scaltriti, M, Carmona, F.J, Toska, E, Cocco, E, Hyman, D, Cutler, R, Avogadri-Connors, F, Wick, M.J, Papadopoulos, K.P, Lalani, A.S, Baselga, J
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Anticancer properties; Antitumor activity; Binding; Biotechnology; Breast cancer; Cancer; Chromatin; Clinical trials; Crosstalk; Deoxyribonucleic acid; DNA; Endocrine therapy; Enhancers; Enzyme inhibitors; ErbB-2 protein; Estrogen receptors; Estrogens; Fulvestrant; Gene expression; Gene sequencing; Genes; Hematology, Oncology and Palliative Medicine; Immunoprecipitation; Inhibition; Kinases; Medical research; Metastases; Mutation; Phenotypes; Protein-tyrosine kinase; Signaling; Therapy; Transcription; Tumors; Tyrosine; Xenografts; Xenotransplantation
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32971-9

Background: Recent large scale next-generation sequencing studies have revealed recurrent activating mutations of ERBB2 (the gene encoding HER2) across a wide variety of cancer types. In metastatic breast cancer, HER2 mutations are typically mutually exclusive with amplification/overexpression and occur predominantly in estrogen receptor positive (ER+) tumors. We have recently reported that inhibition of PI3K in PIK3CA-mutant ER+ cells/tumors leads to a rapid transcriptional rewiring towards a more luminal phenotype. rendering these cells more dependent on ER function and responsiveness to anti-ER therapy. Here, we hypothesize that ER+ HER2-mutant cells show a similar adaptive response to neratinib, an irreversible pan-HER tyrosine kinase inhibitor. Material and Methods: We have established cell lines expressing either wild-type or the most recurrent ERBB2 mutant alleles in ER+ PIK3CA-mutant cell lines. In addition, we have established the same stable clones in ER-negative (ER-) untransformed MCF10A cells to test the oncogenic potential and kinase activity of different ERBB2 mutations. Chromatin immunoprecipitation (ChiP) was used to test the binding of ER to specific regions of DNA. Cell line-based and patient-derived xenografts were also used to test the antitumor activity of neratinib alone and in combination with fulvestrant. Results: In both MCF7 and T47D cells expressing either wild type or mutant ERBB2 we observed that ESR1 {the gene encoding ER) and ER-target genes such as CREB1 were upregulated after 24 hours of neratinib treatment. This effect was barely detectable in control cells stably transfected with the empty vector, suggesting that the increased expression of ER/ER target genes was dependent on the expression of HER2 in these cells. This was accompanied by increased DNA binding of ER to promoters and enhancers of genes regulated by this receptor. Interestingly, neratinib treatment was sufficient to induce the expression of ESR1, CREB1 and other ER-dependent genes also in MCF10A cells expressing mutant HER2. Consistently, the combination of neratinib and fulvestrant was superior to single agent therapy both in ER+ and ER- HER2-driven xenografts. Conclusions: These preclinical studies support the bi-directional signaling that occurs between ER and HER2 (ER/HER2 cross-talk) pathways. Inhibition of HER2 leads to up-regulation of ER signaling, likely as a tumor escape mechanism for growth. Thus, dual blockade of ER and HER2, using fulvestrant a