Molecular alterations in anti-apoptotic BCL2 family proteins in breast cancer cell line models, drug sensitivities and dependencies to guide the development of BCL2 inhibitors

Abstract

BackgroundBreast cancer is one of the most prevalent cancers and a cause of significant morbidity and mortality. Despite introduction of new therapies that improve control of the disease, metastatic breast cancer remains still incurable in most cases. Further therapies based on a better understanding of the pathogenesis of breast cancers and its sub-types are needed to improve outcomes. Apoptosis has arisen as a potential target in recent years. Research on therapeutic use of apoptosis promoting drugs could be advanced by cell line models of efficacy. MethodsAlterations in antiapoptotic members of the BCL2 family of proteins encoded by genes BCL2, BCL2L1, BCL2L2, MCL1 and BCL2A1 were evaluated in breast cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE). Sensitivities of breast cancer cell lines to apoptosis promoting drugs were evaluated using the Genomics of Drug Sensitivity in Cancer (GDSC) platform. Concomitant molecular aberrations of sensitive and resistant cell lines were examined for recurrent themes. Cell line dependencies were surveyed using publicly available CRISPR and RNAi arrays. ResultsBreast cancer cell lines, in concordance with breast cancer patient samples, commonly exhibit amplifications in the BCL2 member MCL1 but not other molecular alterations in antiapoptotic family members. The panel of breast cancer cell lines with sensitivity to drugs inhibiting MCL1, with or without inhibition of other family members consists exclusively of cell lines of the basal phenotype. Sensitive cell lines possess fewer amplifications in the commonly amplified in breast cancer loci at 8q23, 11q13, 17q12 and 1q21. Dependency analysis suggests that in some instances activity of cancer related pathways such as PI3K/ AKT and WNT/ β-catenin may affect apoptosis threshold. ConclusionBreast cancer cell line models faithfully depict the most common molecular aberration in BCL2 family proteins observed in clinical breast cancer samples, MCL1 amplifications. Basal cell lines may be a preferred target of MCL1 inhibitors. However, concomitant aberrations, as explored in this report, are likely to be involved in ultimate sensitivity to anti-apoptosis targeting therapies.