15 April 2024

Researchers have identified pathways in acute myeloid leukaemia (AML) resistance to FLT3 inhibitors, offering hope of new treatments.

According to the international team working on the project, a new generation of drugs could now prevent the resistance found in the form of AML which carry FLT3 internal tandem duplications (FLT3-ITD), a mutation which affects nearly 30% of patients.

The project has involved the universities of Birmingham and Newcastle in the UK, with the Princess Maxima Centre of Paediatric Oncology in Holland and the University of Virginia, USA. There has been further collaboration with the University of Oxford and the Institute of Cancer Research, London.

The researchers replicated the genetic changes that occur in response to FLT3 inhibitor treatment in the laboratory.

Their initial research showed the treatment-resistant cancers activated multiple signalling pathways that overcame the action of the drug.

Targeting RAS family proteins seems to prevent this increased signalling from preventing death of cancer cells. They employed a new drug development technique, called antibody derived technology, to target these RAS proteins.

Researcher Professor Constanze Bonifer, of the University of Birmingham, said: “The pharmaceutical industry had high hopes that drugs targeting aberrant growth factor receptors such as the FLT3-ITD would prevent people from relapse. However, cancer cells are smart, and rewire their growth control machinery to use other growth factors present in the body.

“Targeting RAS family members prevents the cancer from rewiring and using different signalling pathways to escape cell death.”

Professor Terry Rabbitts, from the Institute of Cancer Research, said: “Mutant RAS was considered undruggable, but the antibody technology facilitated the development of the RAS-binding compounds used in the current study of cancer cell re-wiring. Antibody derived technology will allow development of a new generation of drugs to hard-to-drug and intrinsically disordered proteins.”


Coleman DJL, Keane P, Chin PS, Ames L, Kellaway S, Blair H, Khan N, Griffin J, Holmes E, Maytum A, Potluri S, Strate L, Koscielniak K, Raghavan M, Bushweller J, Heidenreich O, Rabbitts T, Cockerill PN, Bonifer C. (2024) “Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.” iScience, doi: 10.1016/j.isci.2024.109576.

Link: https://www.cell.com/iscience/fulltext/S2589-0042(24)00798-3


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