Combination therapy overcomes BET inhibitor resistance

11 Apr 2023
Combination therapy overcomes BET inhibitor resistance

Scientists at St Jude Children’s Research Hospital developed a novel combination therapy approach for a leukaemia subtype harbouring rearrangements in the KMT2A gene.

The approach overcomes the cancer’s drug resistance, without adding toxicity.

The study was published today 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 leukaemia harbouring KMT2A rearrangements.

These rearrangements are often found in infants and can occur in acute lymphoblastic or myelogenous leukaemia (ALL or AML).

“KMT2A rearrangements are enriched in infant leukaemias which generally have a poor prognosis,” said co-corresponding author Jun J Yang, PhD, St Jude 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 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,” Yang added.

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 leukaemia.

The work demonstrated that the combination could impede the growth of leukaemia cells.

“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, St Jude Department of Tumour Cell 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 synergise, but on its own, the GSK3 inhibitor doesn’t seem to have an effect.”

The findings suggest that the combination of BET and GSK3 inhibition holds promise for further development in KMT2A-rearranged leukaemias.

The study’s co-first authors are Shaela Wright, Jianzhong Hu and Hong Wang of St Jude.

The study’s other authors are Marina Konopleva and Steven Kornblau, University of Texas MD Anderson Cancer Center; Rui Lu, O’Neil Comprehensive Cancer Center, University of Alabama at Birmingham; and Judith Hyle, Yang Zhang, Guoqing Du, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz and Beisi Xu of St Jude.

Article: Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukaemia through combinatorial CRISPR screens

Source: St Jude Children's Research Hospital