The evasion of apoptosis is a hallmark of many cancers that allows the inappropriate survival of cancer cells. In addition its critical role in tumor development, the dysregulation of apoptosis in cancer cells also has therapeutic implications as many cytotoxic drugs act by inducing apoptotic cell death. Thus, the subversion of apoptosis often leads to chemoresistance and treatment failures.
To further explore the importance of the dysregulated apoptosis in a range of cancers, we screened the NCI-60 panel of cancer cell lines for their dependence on the pro-survival BCL2 proteins. Initially, we determined their sensitivity to small molecule inhibitors (BH3 mimetic compounds) that target BCL2, BCLxL and/or BCLw), either selectively (e.g. BCL2 itself with venetoclax/ABT-199) or all of them (ABT-737). Our data reveal that only a handful of cell lines are killed when these particular pro-survival BCL2 proteins are targeted and strongly suggest that one of the other pro-survival BCL2 proteins must be limiting the action of these agents. We hypothesize that Mcl-1 could be that factor.
To test that hypothesis, we asked whether deleting the MCL1 gene using CRISPR/Cas9 technology could sensitize these cells to the BH3 mimetic compounds such as ABT-737. Using such a chemo-genomics approach, we anticipate that we will be able, for most of the cancer cell line, to identify which of the pro-survival BCL2 proteins maintain their viability, determine which BH3 mimetic could be utilized to induce apoptosis in them and potentially why such therapy might fail.