Researchers have developed a novel combination therapy approach to help patients with KMT2A-mutated acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) overcome resistance to bromodomain and extraterminal domain (BET) inhibitors without adding toxicity, according to a novel study published by Wright et al in Proceedings of the National Academy of Sciences.
Background
BET inhibitors have been shown to provide therapeutic benefits against many different cancer types. However, the mechanisms governing response and resistance to this class of therapies are poorly understood.
“KMT2A [mutations] are enriched in infant leukemias, which generally have a poor prognosis,” explained co–corresponding study author Jun J. Yang, PhD, Vice Chair of the Department of Pharmacy and Pharmaceutical Sciences and the Endowed Chair in Pharmacogenomics at St. Jude Children’s Research Hospital. “Over the past several decades, there has been very little progress in improving [the] cure rates of infants with KMT2A-[mutated] leukemias, so there is a clear need to develop new therapies for those patients. This is one of the very few genetic abnormalities that can affect ALL and AML, which makes it very interesting from a tumor biology perspective,” he added.
Study Methods and Results
In the new study, the researchers conducted CRISPR screens, performing a genome-wide loss-of-function analysis in patients with KMT2A-mutated ALL or AML. They found that loss of the SPOP gene may cause significant BET inhibitor resistance, which they confirmed in cell lines and xenograft mouse models. Additional CRISPR screens revealed that cells treated with BET inhibitors may be sensitive to disruptions in the gene GSK3B.
The researchers then developed a combination therapy approach using both BET inhibitors and GSK3 inhibitors to target KMT2A-mutated leukemia—demonstrating that the combination therapy could impede the growth of leukemia cells.
Conclusions
“Our expertise in combinatorial CRISPR screens allowed us to identify resistance mechanisms, but by also doing reverse screens, we … identified the targetable options that will allow us to overcome [BET inhibitor] resistance,” highlighted co–corresponding study author Chunliang Li, PhD, Assistant Professor of Tumor Cell Biology at St. Jude Children’s Research Hospital. “Our findings led us to a combination regimen that can reverse resistance to BET inhibition. The BET and GSK3 inhibitor combination shows remarkable efficacy but also no increase in toxicity because the … inhibitors synergize, but on its own, the GSK3 inhibitor doesn’t seem to have an effect,” he noted.
The findings suggested that the combination of BET inhibitors and GSK3 inhibitors may hold promise for further development in KMT2A-mutated leukemias.
Disclosure: The research in this study was supported by the National Institutes of Health, V-Scholar Foundation fund, the American Cancer Society-Hasse Family Glenn Hasse-Research Scholar Grant, and the American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit pnas.org.
