Intracellular targeting of the oncogenic MUC1-C protein with a GO-203 nanoparticle formulation overcomes MCL-1- and BFL-1-mediated resistance in human carcinoma cells.

Abstract

e14053 Background: Aberrant expression of MCL-1 and BFL-1, the pro-survival members of the Bcl-2 family, is a major cause of drug resistance in human cancers. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly expressed in most human carcinomas. Notably, there is no known relationship between the oncogenic MUC1 C-terminal subunit (MUC1-C) and these anti-apoptotic proteins. Methods: MUC1-C was targeted in breast, lung and colon cancer cells by a stable shRNA, a tetracycline-inducible shRNA, or a pharmacologic peptide inhibitor GO-203. MCL-1 was inhibited by siRNA or the MS-1 peptide. In vitro and in vivo studies were conducted using our polymeric nanoparticles (NPs) for intracellular delivery of peptide cargos. Cells were selected for resistance to ABT-737 or ABT-263, which target BCL-2, BCL-XL and BCL-w, but not MCL-1 and BFL-1. Results: Targeting MCL-1 with MS-1/NPs inhibited the survival of parental cancer cells in vitro and in vivo, and was associated with upregulation of BFL-1 levels. In addition, MS-1/NPs treatment had limited effects on ABT-resistant cells because of increased BFL-1 expression. Importantly, we found that targeting MUC1-C is associated with suppression of both MCL-1 and BFL-1. Mechanistically, MUC1-C (i) stabilizes MCL-1 by activating the MEK→ERK and PI3K→AKT pathways, and (ii) induces BFL-1 through the NF-κB p65 pathway. Treatment with GO-203/NPs suppressed proliferation of parental and ABT-resistant cells. In addition, we show that combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and ABT-resistant cells. Conclusions: These findings demonstrate that targeting MUC1-C with GO-203/NPs is a potential strategy for abrogating MCL-1- and BFL-1-mediated resistance.