B302: “Identifying novel transcriptional downregulators of MCL-1 to induce apoptosis in pancreatic cancer”
1University of Liverpool, Liverpool, UK
The anti-apoptotic members of the BCL-2 family of proteins are highly expressed in several cancers and function by sequestering their pro-apoptotic counterparts. Small molecule inhibitors that target specific anti-apoptotic members of the BCL-2 family, such as navitoclax (BCL-2- and BCL-XL-specific) and venetoclax (BCL-2-specific) have been successfully used in chemotherapy. However, antagonising MCL-1, another anti-apoptotic member of the BCL-2 family, has proven to be difficult with small molecule inhibitors. The currently available inhibitors of MCL-1 are not potent enough to be used in a therapeutic context, thus necessitating other ways to inhibit MCL-1. Since MCL-1 is a short-lived protein, we wish to assess if compounds that transcriptionally repress MCL-1 can be used in a therapeutic context in MCL-1-dependent tumours.
Using connectivity mapping, we have identified several chemicals that could potentially affect MCL-1 transcription. Following validation of their efficacy to downregulate MCL-1 and induce apoptosis in a MCL-1-dependent cell line (H23), the compounds have been used in conjunction with A-1331852, a BCL-XL-specific inhibitor in pancreatic cell lines, SUIT-2 and PANC-1, as well as in a primary cell line derived from the genetically engineered mouse model of pancreatic cancer (KPC mice: KrasLSL.G12D/+; p53R172H/+; PdxCretg/+).
Initial screening studies identified doxorubicin, ellipticine, daunorubicin, ivermectin, mitoxantrone and fenbendazole to be potent in downregulating MCL-1 and inducing apoptosis. In the pancreatic cancer cell lines, these compounds were efficacious in inducing apoptosis in combination with A-1331852, suggesting a dependence on both BCL-XL and MCL-1 for survival in pancreatic cancer.
These results indicate that translational repression of MCL-1 in combination with BCL-XL inhibition could be successfully used to induce apoptosis in pancreatic cancer cell lines. This observation will be followed by in vivo studies in relevant mice models to study the therapeutic potential of this combination in pancreatic cancer.