Abstract 2314: Novel BH3 mimetic based therapeutic strategies for the treatment of breast cancer
Authors: Kratche Zachary , Adams MacKenzie , Wilson Robert , Ethier Stephen , Guest Stephen 
Published: July 2017

Bcl-2 homology domain 3 (BH3) mimetics are a new class of targeted anti-cancer compounds that function by inducing cancer cell apoptosis. Testing in a variety of pre-clinical tumor models has shown that BH3 mimetics are capable of inducing remarkable tumor regressions. Recently, a clinical trial of the BH3 mimetic venetoclax in Chronic Lymphocytic Leukemia (CLL) resulted in an impressive response rate of 80% leading to FDA approval. Using unbiased genomic and functional genomic approaches, we identified gene amplification of the BCL2L1 gene, which encodes the anti-apoptotic protein BCL-XL, as a novel driver event in breast cancer. We identified focal amplification of the BCL2L1 gene in the SUM-185 breast cancer cell line and a genome-wide RNAi-based screen identified BCL2L1 as one of the top genes necessary for viability of this cell line (ranked 5th out of 15,256 genes). Treatment of SUM-185 cells with navitoclax showed that these cells are intrinsically sensitive to this drug (IC50 = 100nM). This sensitivity was 1-2 logs greater than what was observed for breast cancer cell lines that do not harbor BCL2L1 gene amplification. To expand the relevance of these findings beyond the SUM-185 cell line, we used the cancer cell line encyclopedia (CCLE) database to identify an additional breast cancer cell line, HCC38, that also harbors a focal BCL2L1 gene amplification. Treatment of HCC38 cells with navitoclax revealed a high level of sensitivity that was equivalent to that of SUM-185 cells. These findings demonstrated that a subset of breast cancers that harbor BCL2L1 gene amplification are highly sensitive to a BH3 mimetic that targets BCL2L1 suggesting that BH3 mimetics could be used as a single agent to effectively treat these breast cancers. We also examined the effectiveness of BH3 mimetics when used as part of a combination therapy approach. In addition to a focal amplification of the BCL2L1 gene, the SUM-185 breast cancer cell line also harbors a focal amplification of the fibroblast growth factor receptor 3 (FGFR3) gene as well as an activating mutation in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene. Treatment of SUM-185 cells with low doses of navitoclax, a FGFR inhibitor, or a PIK3CA inhibitor had little effect on colony forming efficiency. At these same low doses, combined treatment with navitoclax and the FGFR inhibitor or the PIK3CA inhibitor resulted in a strikingly synergistic effect with near complete loss of colony forming ability (less than 10% of controls). We further showed that this loss of clonogenicity was the result of a rapid induction of apoptosis by the combination therapies. These results suggest that combining BH3 mimetics with inhibitors of PIK3CA or FGFR is a promising novel therapeutic strategy for a subset of breast cancer patients.

Citation Format: Zachary Kratche, MacKenzie Adams, Robert Wilson, Stephen Ethier, Stephen Guest. Novel BH3 mimetic based therapeutic strategies for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2314. doi:10.1158/1538-7445.AM2017-2314