Combination therapy overcomes BET inhibitor resistance

May 5, 2023
Scientists at St. Jude Children’s Research Hospital have shown how combining BET and GSK3 inhibitors impedes the growth of KMT2A rearranged leukemia.

Scientists at St. Jude Children’s Research Hospital developed a novel combination therapy approach for a leukemia subtype harboring rearrangements in the KMT2A gene. The approach overcomes the cancer’s drug resistance, without adding toxicity. The study was published in Proceedings of the National Academy of Science. 

Bromodomain and extra-terminal domain (BET) inhibitors have been shown to provide therapeutic benefits against many different cancers. However, the mechanisms governing response and resistance to this class of therapies are poorly understood. 

Scientists at St. Jude conducted CRISPR screens, performing a genome-wide loss of function analysis in leukemia harboring KMT2A rearrangements. These rearrangements are often found in infants and can occur in acute lymphoblastic or myelogenous leukemia (ALL or AML). 

The researchers found that loss of the SPOP gene causes significant BET inhibitor resistance, which they confirmed in cell lines and xenograft mouse models. Additional CRISPR screens revealed that cells treated with BET inhibitors are sensitive to disruptions in the gene GSK3B. 

Armed with this information, the researchers developed a combination therapy approach that uses both BET and GSK3 inhibitors against KMT2A mutated leukemia. The work demonstrated that the combination could impede the growth of leukemia cells. 

St. Jude release