BH3 mimetics like ABT-263 induce apoptosis in subsets of cancer. However, they have shown limited clinical efficacy as single agents, and rational combination strategies remain underexplored. Toward the development of a novel combined therapy, we examined efficacy of ABT-263 across 331 cancer cell lines. Cell lines with high expression levels of the pro-apoptotic gene BIM were more sensitive to ABT-263 activity. This was particularly evident in small cell lung cancer (SCLC), which tends to have higher BIM levels and is among the most sensitive to ABT-263. However, MCL-1 expression mitigated the impact of ABT-263-induced apoptosis by sequestering BIM released from BCL-2 and BCL-XL. Since MCL-1 expression is dependent on TORC1 activity in some cancers, we attempted to overcome the apoptotic block in SCLC by combining ABT-263 with the TORC1/2 inhibitor AZD8055. AZD8055 treatment alone downregulated MCL-1 expression; combination AZD8055 and ABT-263 induced marked apoptosis and growth arrest in vitro, as well as tumor regressions in multiple SCLC xenograft models. Strikingly, low-dose AZD8055 was sufficient to promote tumor regressions in the combination strategy. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve single-agent ABT-263 activity in SCLC.
Citation Format: Anthony C. Faber, Carlotta Costa, Anahita Dastur, Cyril Benes, Jeffrey Engelman. Assessment of ABT-263 activity across a comprehensive cancer cell line collection leads to a novel, potent combination therapy for small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2933. doi:10.1158/1538-7445.AM2014-2933