Evasion of apoptosis is a known feature of cancer cells. One mechanism of deregulating the apoptotic pathway is through overexpression of anti-apoptotic Bcl-2 family members. ABT-263 is a first-in-class Bcl-2 family inhibitor that restores the ability of cancer cells to undergo apoptosis. However, many cancer cells are resistant to ABT-263 due to high levels of a Bcl-2 family member Mcl-1, which is not targeted by the drug. Mcl-1 expression is known to be regulated transcriptionally, translationally, and through proteosome-mediated degradation. Recently, Mcl-1 expression was shown to be affected by microRNAs (miRNAs). In order to identify miRNAs that modulate the sensitivity of cancer cells to ABT-263, we screened a library of 810 human miRNA mimics in HCT-116 cells in the presence of ABT-263. The screen revealed 19 miRNAs that sensitize HCT-116 cells to ABT-263. Fifteen of these miRNAs were also shown to sensitize CHL1 melanoma cells to the same agent. We further evaluated twelve of the strongest sensitizers in these cell lines. We found that these sensitizers induced apoptosis only in the presence of ABT-263. In addition, while all twelve of these miRNAs reduced Mcl-1 protein expression, only ten of them targeted Mcl-1 through direct binding to the Mcl-1 3′ untranslated regions (3′-UTR) of the gene. Other resistance pathways and regulators of Mcl-1 expression may be identified using this method. Our data can be used to design miRNA replacement therapies to increase sensitivity to Bcl-2 antagonists. The expression of the 12 marker microRNAs is now being correlated to the sensitivity to ABT-263 in order to enable rational patient selection in ABT-263 clinical trials.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):B4