Evasion from apoptosis is a key hallmark of cancer. Drugs, termed BH3-mimetics, have been developed that can bind to select BCL-2 pro-survival family proteins and induce death of cancer cells. The leading drug is called Venetoclax, which binds to BCL-2, and is currently FDA approved for treatment of refractory Chronic Lymphocytic Leukemia and is in clinical trials for additional cancers. However, several other tumour types depend instead on the related pro-survival protein MCL-1 for sustained growth, including MYC-driven aggressive B cell lymphomas. BH3-mimetics that specifically target MCL-1 have recently been developed and tested in pre-clinical models, and three such drugs have entered clinical trials for Acute Myeloid Leukemia, Multiple Myeloma, and B cell lymphomas.
These drugs bind with higher affinity to human MCL-1 protein over mouse Mcl-1 protein, so current mouse models of cancer may not accurately predict the therapeutic potential of these drugs. To address this, we have generated a highly accurate pre-clinical mouse model that expresses human (hu)MCL-1 protein to test the potential of MCL-1 targeting BH3-mimetics, alone and in combination with standard-of-care agents, for therapy of lymphomas. Furthermore, we have carried out whole genome CRISPR/Cas9 screens in pre-clinical models of aggressive MYC-driven lymphomas to predict resistance factors to MCL-1 targeting BH3-mimetics. Understanding the molecular basis of these resistance factors will enable us to design therapeutic strategies to overcome them, thereby informing future clinical trials with MCL-1 targeting BH3-mimetics.