Scientists at St. Jude Children’s Research Hospital have developed a novel combination therapy for a leukemia subtype harboring rearrangements in the KMT2A gene, which is more common in infants. The combination uses BET- and GSK3-inhibitors. The researchers report that based on laboratory work, their “synergistic” combinatorial approach overcomes the cancer’s drug resistance without adding toxicity.
The study was published this week in Proceedings of the National Academy of Science.
The scientists started by conducting CRISPR screens, looking at genome-wide loss of function analysis in leukemia harboring KMT2A rearrangements. These rearrangements can occur in acute lymphoblastic or myelogenous leukemia (ALL or AML). About 62,000 people per year are diagnosed with leukemia in the U.S. alone. While the five-year relative survival rate has increased dramatically, there are still resistant forms of the disease.
“KMT2A rearrangements are enriched in infant leukemias which generally have a poor prognosis,” said co-corresponding author Jun J. Yang, PhD, departments of pharmacy and pharmaceutical sciences and oncology. “Over the past several decades, there has been very little progress in improving cure rates of infants with KMT2A-rearranged 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,” Yang added.
The authors note that mix lineage leukemia (MLL)/KMT2A-rearranged leukemia are one of the most refractory acute leukemia subtypes. They comprise approximately 10 percent of human leukemia cases, including more than 80% of infant cases and make up approximately five to ten percent of ALL or AML cases.
The St. Jude researchers found that loss of the SPOP gene causes significant bromodomain and extra-terminal domain (BET) inhibitor resistance. They confirmed this finding in cell lines and xenograft mouse models. Additional CRISPR screens revealed that cells treated with BET inhibitors are sensitive to disruptions in the gene serine/threonine glucogen synthase kinase-3 (GSK-3). Pharmaceutical inhibition of GSK3 reversed the BET inhibitor-resistance phenotype.
Based on these findings, the researchers developed a combination therapy approach using both BET- and GSK3-inhibitors against KMT2A mutated leukemia. The work demonstrated that the combination could impede the growth of leukemia cells.
BET proteins’ functions include initiation and elongation of transcription and cell cycle regulation. As anticancer agents, these inhibitors preferentially bind to superenhancers—noncoding regions of DNA critical for the transcription of genes that determine a cell’s identity.
GSK-3 inhibitors, meanwhile, performs critical functions in many cellular processes, such as apoptosis, tumor growth, cell invasion, and metastasis.
“Our expertise in combinatorial CRISPR screens allowed us to identify resistance mechanisms, but by also doing reverse screens, we also identified the targetable options that will allow us to overcome resistance,” said co-corresponding author Chunliang Li, PhD, Department of Tumor Biology. “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 GSK3 and BET inhibitors synergize, but on its own, the GSK3 inhibitor doesn’t seem to have an effect.”