Abstract 2160: Targeting SMC1 in combination therapy for triple negative breast cancer (2016)

Abstract Triple negative breast cancer (TNBC) defined primarily by lack of expression of estrogen and progesterone hormone receptors (HR) and lacking HER2 overexpression and/or gene amplification (HER2) is an aggressive subtype with poor prognosis. Presentation is frequently at an advanced stage, and TNBC is particularly prevalent in younger women, African Americans, and/or in women with BRCA1 and less frequently with BRCA2 gene mutations. Over the last several years, although great progress has been made in the treatment of early HR positive and HER2+ (as well as advanced stage) breast cancer, relapse/progression-free and overall survival of patients with TNBC remains a serious problem. Molecular subtyping identified subsets of TNBC, several of which are thought to be DNA-repair deficient (either due to germ-line mutations such as BRCA1 or 2, or somatic mutations affecting DNA-repair), may be amenable to treatment with DNA-damaging agents such as platinum compounds and PARP (poly(ADP-ribose) polymerase-1) inhibitors. This could be particularly useful in BRCA-mutated cancers. As for the other TNBC subtypes, development of novel therapeutic agents, represents a high priority. In response to this clinical need, we tested the efficacy of a novel combinatorial strategy which targets differentiated cells and TNBC cancer stem cell like population (CSCs). Structural maintenance of chromosome-1 (SMC1) was selected as a tumor antigen based on our published studies showing its surface localization and the role in cell proliferation, survival and metastasis in TNBC cells. Bioinformatics analyses using public available patient cohorts with clinicopathological information such as TCGA, NCBI and BRAVO showed statistically higher mRNA overexpression of SMC1 in TNBC compared to HR+ and HER2+ breast cancer. To target SMC1, we developed several monoclonal antibodies against the epitope of SMC1 which showed similarity to cell-adhesion peptides in order to facilitate biochemical and cellular assays. The impact of SMC1 inhibition in combination with veliparib, an inhibitor of PARP-1 was tested in BRCA1-wild-type (MDA-MB-231) vs. mutant (MDA-MB-436) TNBC cells and in CSCs (CD44+/CD24low-) sorted from these cells by MTT and colony forming assays. TUNEL and Annexin-V flipping assays were used to determine cell apoptosis. The role of intrinsic vs. extrinsic pathways of apoptosis was examined by measuring activation of Caspase 8 and 9 as well as measurements of cytochrome-c release from mitochondria. Our results showed that Mab-S15 recognizes SMC1 which is selectively expressed on the surface of cancer cells (including CSC’s) and differentiated TNBC’s, but has a minimal distribution in normal cells. The antibody distinctly inhibits the survival of TNBC in culture, including CSC’s, sorted from TNBC’s. The Mab-S15 and veliparib combination was more effective than the individual agents in inhibiting the growth and survival of TNBC cells including those with a functional BRCA1. Citation Format: Sushma Yadav, David Berz, George Somlo, Kimlin Ashing, Yate-Ching Yuan, Robert J. Hickey, Sailee Yadav, Arthur D. Riggs. Targeting SMC1 in combination therapy for triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2160.