L Walsh, KE Haley, B Moran, B Mooney, F Tarrant, SF Madden, A Di Grande, Y Fan, S Das, OM Rueda, CM Dowling, D Varešlija, S-F Chin, SC Linn, LS Young, K Jirström, J Crown, R Bernards, C Caldas, WM Gallagher, DP O'Connor, T Ni Chonghaile
Clin Cancer Res
PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in ER-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extra-terminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC. EXPERIMENTAL DESIGN: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy number alterations and RNA-seq on 61 ILC patient samples. RESULTS: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on anti-apoptotic proteins and a transcriptional rewiring inducing Fibroblast Growth Factor Receptor 1 (FGFR1). This increase in FGFR1was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitor was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% hadFGFR1amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC. CONCLUSIONS: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.