Bypassing drug resistance by triggering necroptosis: recent advances in mechanisms and its therapeutic exploitation in leukemia

Resistance to regulated cell death is one of the hallmarks of human cancers; it maintains cell survival and significantly limits the effectiveness of conventional drug therapy. Leukemia represents a class of hematologic malignancies that is characterized by dysregulation of cell death pathways and treatment-related resistance. As the majority of chemotherapeutic and targeted drugs kill leukemia cells by triggering apoptosis, the observed resistance indicates the need for novel therapeutic strategies to reactivate nonapoptotic cell death programs in refractory leukemia. Necroptosis is a regulated form of necrosis that is precisely modulated by intracellular signaling pathways and thus provides potential molecular targets for rational therapeutic intervention. Indeed, accumulating evidence indicates that many current antitumor agents can activate necroptotic pathways and thereby induce leukemia cell death. Elucidation of the complete regulatory mechanism of necroptosis is expected to accelerate the development of novel therapeutic strategies for overcoming apoptosis resistance in leukemia. Here, we review the latest research advances in the regulatory mechanisms of necroptosis and summarize the progression of necroptosis-based therapeutic strategies in leukemia.