Researchers have identified a potential combination therapy that could help babies and young children with a type of leukaemia that has a poor prognosis.
Scientists at St Jude Children’s Research Hospital, USA, say their experimental therapy could target leukaemias that harbour rearrangements in the KMT2A gene and overcome the cancer’s drug resistance, without adding toxicity.
Dr Jun J. Yang from St Jude Departments of Pharmacy and Pharmaceutical Sciences and Oncology, and co-leader of the study, said: “KMT2A rearrangements are enriched in infant leukaemias, which generally have a poor prognosis.
“Over the past several decades, there has been very little progress in improving cure rates of infants with KMT2A-rearranged leukaemias, 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 tumour biology perspective.”
Bromodomain and extra-terminal domain (BET) inhibitors provide therapeutic benefits against many different cancers, but the mechanisms governing response and resistance to this class of therapies are unknown.
The study, published in Proceedings of the National Academy of Science, used CRISPR screens, performing a genome-wide loss of function analysis in leukaemia harbouring KMT2A rearrangements.
They found that loss of the SPOP gene causes significant BET inhibitor resistance, which was then confirmed in cell lines and xenograft mouse models. Further CRISPR screens showed cells treated with BET inhibitors are sensitive to disruptions in the gene GSK3B.
The researchers used this knowledge to develop a combination therapy approach that uses both BET and GSK3 inhibitors against KMT2A-rearranged leukaemia, and found it could impede the growth of leukaemia cells in mouse models.
Dr Chunliang Li from St. Jude Department of Tumor Cell Biology, who co-led the study with Dr Yang, said: “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.
“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 synergise, but on its own, the GSK3 inhibitor doesn’t seem to have an effect.”
Wright S, Hu J, Wang H, Hyle J, Zhang Y, Du G, Konopleva MY, Kornblau SM, Djekidel MN, Rosikiewicz W, Xu B, Lu R, Yang JJ, Li C. (2023) “Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens.” Proceedings of the National Academy of Sciences, doi: 10.1073/pnas.2220134120.
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