According to recent research, relapses in a common kind of leukemia may be avoidable since it has revealed how the illness becomes resistant to first-line therapy.
Researchers from the Princess Maxima Centre of Pediatric Oncology, the University of Virginia, the Institute of Cancer Research (ICR), the University of Birmingham, and Newcastle University have identified alterations in a mutated form of acute myeloid leukemia (AML) samples from patients who relapsed after receiving FLT3 inhibitor treatment. Their findings were published in iScience.
The researchers discovered that the genetic alteration could be reproduced in laboratory experiments and that the resistant malignancy had up-regulated a number of alternative signalling pathways to evade the effects of the medication.
These experiments showed that increased signalling was no longer able to prevent the cells from dying when targeting RAS family proteins with a small molecule inhibitor that Terry Rabbitts’ team at the Weatherall Institute of Molecular Medicine, University of Oxford, and the ICR developed from a chemical library screen using the paratope of an inhibitory intracellular antibody.
The transcription factors RUNX1 and AP-1 were found to be crucial to mediating drug resistance by the researchers. Only when growth factor signaling is present do the two factors work together and bind to their target genes.
Targeting FLT3 causes the cell to reorganize, which in turn causes the overexpression of other genes linked to the signalling cascade and the restoration of AP-1 and RUNX1 binding. RAS is a crucial part of many signalling pathways. By blocking this restoration of RUNX1 binding, drugging RAS stopped growth factor-induced signalling from saving the cancer cells from apoptosis.
Professor Constanze Bonifer at the University of Melbourne, and is one of the senior authors of the paper mentioned, “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.”
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