The evasion of apoptosis is a hallmark of many cancers since this permits the inappropriate survival of cancer cells. Moreover, as many cytotoxic drugs act by inducing apoptotic cell death, the subversion of apoptosis often leads to chemoresistance.
To further explore the importance of the deregulation of apoptosis in diverse cancers, we screened the NCI-60 panel of cancer cell lines for their dependence on Bcl‑2 or its pro-survival relatives (Bcl‑xL, Bcl‑w, Mcl‑1) by determining their sensitivity to BH3 mimetic compounds. These novel agents act to inhibit Bcl‑2 or its relatives by mimicking the action of the BH3-only proteins, their natural antagonists. Strikingly, only a few cell lines in the NCI-60 panel were readily killed by ABT-737 (targeting Bcl‑2, Bc‑xL and Bc‑w), venetoclax (ABT‑199; to target Bc‑2) or A-1335463 (to target Bc‑xL). These results suggest that pro-survival proteins not targeted by these compounds could be limiting their action. We hypothesized that Mcl-1 could be the likely candidate.
To test that hypothesis, we asked whether deleting the Mcl‑1 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 each of the cancer cell line, to identify which of the pro-survival Bcl‑2 proteins maintain their viability, determine which BH3 mimetic could be utilized to induce apoptosis in them and potentially why such therapy might fail.