Abstract 420: Preclinical evaluation of the SF3B1 inhibitor E7107 in triple negative breast cancer

Abstract

Abstract Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer and account for roughly 15% of human breast cancers. No effective targeted therapies are currently available against these tumors, at least in part due to their genetic and epigenetic heterogeneity. Yet, TNBCs are commonly enriched for cells arrested in a progenitor-like state. We therefore performed a genome-wide siRNA lethality screen to identify selective TNBC dependencies associated with this particular phenotype in vitro. These studies led to the identification of several spliceosome genes, including the core splicing factor SF3B1, as selectively and recurrently essential for progenitor-like (or basal-A) TNBC cell lines. On this basis, we examined the antitumor effect of E7107, a clinically tested SF3B1 inhibitor, on multiple TNBC cell lines. In vitro, treatment with E7107 for 24-48 hr selectively killed basal-A cell lines relative to differentiated luminal cell lines, decreasing viability by ≈40% or more in 5 of 6 basal-A lines tested. E7107-treated cells appeared to die of apoptosis based on immunoblotting for multiple apoptotic markers. In mice, E7107 (5 mg/kg i.v. for 4 consecutive days) suppressed the growth of preformed tumors by ≈80% and ≈50% in 2 different cell-line-derived xenograft models and was remarkably well-tolerated at this dose. Of note, tumor response in vivo closely mirrored cell sensitivity in vitro, suggesting that in vitro analysis provides a fair estimate of TNBC response to E7107 in mice. Amongst 2 additional patient-derived xenograft (PDX) models tested, E7107 inhibited tumor growth by ≈50% in one model. Thus, E7107 was therapeutically active against 3 of 4 xenograft models tested. Preliminary mechanistic studies in vitro and in vivo pointed to MCL1 inactivation as a major mechanism of action of E7107 in top responders. Together, these data suggest that the spliceosome is a druggable target in TNBC, and that E7107 or similar SF3B1 inhibitors could be effective in a TNBC subset that needs to be further defined. Citation Format: Praveen Sridhar, Stefanie Chan, Ying-Jie Lock, Fabio Petrocca. Preclinical evaluation of the SF3B1 inhibitor E7107 in triple negative 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 420. doi:10.1158/1538-7445.AM2017-420