Abstract 2064: SF3B1 inhibitors sensitize head and neck squamous cell carcinoma to Bcl-xL inhibition by regulating Mcl-1 alternative splicing.

This study explored the application of the alternative splicing of Bcl-2 family protein Mcl-1 in combination chemotherapy for head and neck squamous cell carcinoma (HNSCC) cell lines: meayamycin B (SF3b inhibitor) switched the pre-mRNA alternative splicing of Mcl-1 from anti-apoptotic to pro-apoptotic; the combination of meayamycin B with ABT-737 (Bcl-x_L inhibitor) rapidly stimulated apoptosis in a panel of HNSCC cells, overcoming the HPV-16-mediated Mcl-1 over-expression.

Western blotting and semi-quantitative RT-PCR as well as qPCR afforded evaluation of the expression of Mcl-1 splicing variants at mRNA and protein levels. Apoptosis status was monitored by using caspase 3/7 activity assays and Annexin V/7-AAD staining. siRNA was used to specifically knock down HPV-16 E6 gene.

Meayamycin B exhibited 0.1-10 nM ED₅₀ values in HNSCC cell lines that are mostly resistant to ABT-737. In HPV-16 positive HNSCC, E6 oncogene affords moderate resistance to meayamycin B. The combination of meayamycin B and ABT-737 synergistically induced apoptosis in HNSCC cell lines regardless of HPV status. These data demonstrate the potential of meayamycin B, both as a single agent and in combination with Bcl-x_L inhibitors, for both research and targeted molecular therapeutic purposes for HNSCC.

Citation Format: Yang Gao. SF3B1 inhibitors sensitize head and neck squamous cell carcinoma to Bcl-xL inhibition by regulating Mcl-1 alternative splicing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2064. doi:10.1158/1538-7445.AM2013-2064