A patient-selection strategy for the clinical development of MCL1 inhibitors

Inhibition of apoptosis is a critical step in the pathogenesis of cancers, and is a major barrier to effective treatment. It is now thought that one or more components of the apoptosis pathway are dysregulated in all cancers either by genetic mutation of the genes encoding these proteins (e.g., point mutations, copy-number abnormalities, or chromosomal translocation) or by other mechanisms (e.g., epigenetic mechanisms or upstream oncogenic mutations). Despite this central importance in the development and maintenance of cancer, few apoptosis-targeted therapeutics have reached clinical evaluation.

MCL1, which encodes the anti-apoptotic protein MCL1, is among the most frequently amplified genes in human cancer. A chemical genomic screen identified compounds, including anthracyclines, that decreased MCL1 expression. Genomic profiling indicated that these compounds were global transcriptional repressors that preferentially affect MCL1 due to its short mRNA half-life. Transcriptional repressors and MCL1 shRNAs induced apoptosis in the same cancer cell lines and could be rescued by physiological levels of ectopic MCL1 expression. Repression of MCL1 released the pro-apoptotic protein BAK from MCL1, and Bak deficiency conferred resistance to transcriptional repressors. A computational model, validated in vivo, indicated that high BCL-xL expression confers resistance to MCL1 repression, thereby identifying a patient-selection strategy for the clinical development of MCL1 inhibitors.

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Dr Guo Wei et al. have elucidated a strategy for the development of MCL1 inhibitors as cancer therapeutics. The multiplexed, gene-expression-based high-throughput screening approach holds promise for the future discovery of specific inhibitors of MCL1 expression and for the use of chemical genomic approaches to elucidate small-molecule mechanisms of action. Their study also highlights the power of genomically characterized cell lines for the discovery of predictive biomarkers of drug response. Most immediately, their work suggests an approach to the clinical development of any MCL1 inhibitor in breast and NSCLC tumors, focusing on tumors expressing low levels of BCL-xL as a patient-selection strategy.

Reference:

Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency. Cancer Cell. 2012 Apr 17;21(4):547-62.