Last but not least: BFL-1 as an emerging target for anti-cancer therapies

Bfl-1 is an understudied pro-survival Bcl-2 protein. The expression of Bfl-1 is reported in many cancers, but it is yet to be clarified whether high transcript expression also always correlates with a pro-survival function. However, recent applications of BH3-mimetics for the treatment of blood cancers identified Bfl-1 as a potential resistance factor in this type of Cancer. Hence, understanding the role of Bfl-1 in human cancers and how its up-regulation leads to therapy resistance has become an area of great clinical relevance. In addition, deletion of the murine homologue of Bfl-1, called A1, in mice showed only minimal impacts on the well-being of these Animals, suggesting drugs targeting Bfl-1 would exhibit limited on-target toxicities. Bfl-1 therefore represents a good clinical Cancer target. Currently, no effective Bfl-1 inhibitors exist, which is likely due to the underappreciation of Bfl-1 as a potential target in the clinic and lack of understanding of the Bfl-1 protein. In this review, the roles of Bfl-1 in the development of different types of cancers and drug resistant mechanisms are discussed and some recent advances in the generation of Bfl-1 inhibitors highlighted.

BCL-2 proteins; cancer; cell death; chemotherapy.