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

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

Splicing dysregulation as a driver of breast cancer

“…This could be explained due to the increased burden put on the spliceosome when the rate of transcription is increased due to MYC signalling. Recently, knockdown of SF3B1 was found to result in apoptosis in TNBC with MCL-1 inactivation being a likely mechanistic explanation, given MCL-1 is a SF3B1 splicing target ( Gao & Koide 2013 , Sridhar et al . 2017 ).…”

Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations

“…Moreover, as MDS clones harboring splicing factor mutations may be preferentially sensitive to inhibition of the RNA splicing process compared to the unmutated stem/progenitor compartment [ 30 ], several drugs targeting the splicing machinery are currently evaluated in clinical trials. In particular, a variety of natural products and their derivatives that bind to the SF3B complex and inhibit pre-mRNA splicing at an early step of spliceosome assembly were discovered, including pladienolides, E7107, FR901464, spliceostatin A, herboxidiene, and sudemycin D6 (in Table 2 ) [ 87 , 88 , 89 , 90 , 91 ]. Extensive efforts have been made in the last few years to examine if these small chemicals have antitumor activity in MDS/AML patients [ 87 , 88 ].…”