Abstract 13: Chemical genomics identifies MCL1 repressors and resistance mechanism

Dysregulated apoptotic mechanisms are central to the pathogenesis and maintenance of cancer, and are major barriers to effective treatment. The BCL2 gene family, comprised of both pro- and anti-apoptotic members, controls the intrinsic activation of apoptosis. Amplification of one of the anti-apoptotic members of this pathway, MCL1, constitutes one of the most frequent somatic genetic events in cancer. However, the design of small molecules targeting MCL1 has proven difficult, and the genomic determinants of MCL1 dependence are not well-understood. Furthermore, the contribution of MCL1 regulation in current chemotherapy drug action remains undefined. We therefore developed a chemical genomic approach to identify repressors of MCL1. We measured gene expression levels of all BCL2 family members upon treatment with 2,922 small molecules, including the majority of FDA-approved drugs. We indentified several small molecules inhibiting MCL1 expression, including a few widely used chemotherapy drugs and a natural product triptolide. Those compounds all share similar apoptotic profile when they were tested in panels of cell lines. Genomic profiling indicated that those compounds were global transcriptional repressors (TR). Nevertheless, MCL1 was among the most repressed genes. To further define the contribution of MCL1 repression by those TR compounds, we compared the sensitivity to TRs and MCL1 knockdown. Sensitivity to all TRs correlated with sensitivity to MCL1 knockdown by shRNA; and there is no additive effect of TRs and MCL1 shRNAs. Furthermore, ectopic expression of physiological levels of MCL1 rescued cells from TRs. Triptolide was able to inhibit tumor growth and promote survival in a mouse xenograft model that is sensitive to TR in vitro. Whole genome expression analysis revealed genomic features that correlated with sensitivity to these compounds and to MCL1 shRNAs, and may shed light on biomarker selection when targeting MCL1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 13. doi:10.1158/1538-7445.AM2011-13