Fig. 4

Heterogeneous BCL-2 family dependency profiles direct the application strategies for MCL-1 inhibitors in cancer. The prospects of MCL-1 inhibitors are closely linked to the mitochondrial priming status of tumor cells. In principle, cancerous cells are primed for apoptosis as compared to healthy cells due to the, e.g., oncogene associated upregulation of the apoptosis machinery. This leads to a tight balance between pro-survival and pro-apoptotic proteins. Hematopoietic cancer cells are typically more primed than solid tumors due to the interconnectedness between age, tissue location and priming status (Sarosiek et al. 2017, Cancer Cell). Consequently, MCL-1 inhibitors have great potential as single-agent therapies in primed, strongly MCL-1-dependent cancers (left panel). In tumors with either moderate priming status (e.g., solid tumors) or primed, but MCL-1 co-dependent status, combination therapies are of maximal benefit (mid panel). In primed co-dependent cells, the addition of alternative BH3-mimetics (e.g., venetoclax) is a promising strategy. In solid tumors with moderate priming, chemotherapies can lead to the upregulation of pro-apoptotic BH3-only proteins (e.g., BIM) and thus prime tumor cells for apoptosis, which can be exploited by the addition of MCL-1 inhibitors. Finally, MCL-1 inhibitors are not effective in tumor cells with weak/no MCL-1 dependency (right panel). These cells can be either targeted by alternative BH3-mimetics (e.g., primed BCL-2 dependent cells) or alternative therapy classes to tackle apoptosis refractory cells. The latter are characterized by a loss of effector molecules (BAK, BAX), downregulation of pro-apoptotic BH3-only proteins (e.g., BIM) and/or the occurrence of inactivating mutations (e.g., BAK mutations). The precise targeting of apoptosis refractory cells therefore remains a major challenge irrespective of the availability of BH3-mimetics. This view on the application strategies of MCL-1 inhibitors is based on the work by Kristopher Sarosiek and Anthony Letai, recently reviewed by Singh et al. (Nat Rev Mol Cell Biol, 2019)