Relapses in a common type of leukemia might be avoidable thanks to recent research that has pinpointed how the cancer becomes resistant to initial treatments. The study, published in iScience by researchers from the University of Birmingham, the Institute of Cancer Research (ICR), Newcastle University, the Princess Maxima Centre of Pediatric Oncology, and the University of Virginia, discovered alterations in a certain form of the cancer.Mutated form of acute myeloid leukemia (AML) samples from patients who relapsed after receiving FLT3 inhibitor treatment.
The researchers discovered that the resistant cancer had activated several other signaling pathways to counteract the drug’s effects, and that the genetic alteration was able to be duplicated in laboratory tests.
These studies demonstrated that by targeting RAS family proteins with a small molecule inhibitor created from a chemical library screen using the paratope of an inhibitory intracellular antibody developed by Terry Rabbitts’ team at the Weatherall Institute of Molecular Medicine University of Oxford and the ICR. This increased signal.The researchers found that the drugs targeting FLT3 caused a rewiring of the cells, leading to the upregulation of other genes associated with signalling pathways. This ultimately restored the binding of the transcription factors AP-1 and RUNX1. However, when RAS, a key component in multiple signalling pathways, was targeted with drugs, it prevented the restoration of RUNX1 binding. As a result, the signalling from growth factors was no longer able to rescue the cancer cells from cell death.The pharmaceutical industry had high hopes that drugs targeting abnormal growth factor receptors like FLT3-ITD would prevent relapse,” said Professor Constanze Bonifer from the Institute of Cancer and Genomic Sciences at the University of Birmingham, who is now at the University of Melbourne and is one of the senior authors of the paper. “However, cancer cells are clever and adapt their growth control machinery to utilize other growth factors in the body. Targeting RAS family members prevents cancer cells from adapting and using different signaling pathways to evade cell death.
Targeting RAS has been shown to prevent rewiring and ultimately lead to cancer cell death.
In this study, small molecule inhibitors were utilized to target RAS. These inhibitors were developed using intracellular antibody technology, which involves screening numerous antibody fragments to identify those that bind to the target protein in cells and prevent their protein-protein interactions. Small molecule inhibitors can be screened from chemical libraries that interact with the parts of the target protein where these antibody fragments bind, known as the paratope. Thanks to the natural specificity of these antibody fragments, they are able to effectively target RAS and prevent rewiring.this technology, known as Antibody-derived or Abd technology, can be utilized to focus on proteins that are challenging to drug and discover new regions of the protein that can be targeted to prevent protein-protein interactions.
Professor Terry Rabbitts from the Institute of Cancer Research, who created these medications, stated:
“The advantage of the Antibody-derived technology approach is that intracellular antibodies can be selected for virtually any protein. Subsequently, their specific binding sites can be used to select chemical compounds for drug discovery against proteins that are difficult to drug. Mutant RAS was mentioned as an example.
So far, certain proteins such as RAS have been considered undruggable, but the Abd technology facilitated the development of the RAS-binding compounds used in the current study of cancer cell re-wiring. Abd technology will allow development of a new generation of drugs to hard-to-drug and intrinsically disordered proteins.”
AML with a FLT3-ITD mutation occurs in nearly 30% of all patients and is a highly aggressive disease with a poor prognosis. This genetic change causes the expression of a mutant growth factor receptor which is always active and therefore cancer cells expressing it grow uncontrollably. While inhibitors which specifically target the FLT3 protein are now in use in
Paraphrased: In the past, certain proteins like RAS were seen as impossible to drug, but the Abd technology has enabled the creation of RAS-binding compounds for the current study of cancer cell re-wiring. This technology will lead to the development of a new generation of drugs for proteins that are difficult to drug and inherently disordered.”
AML with a FLT3-ITD mutation appears in almost 30% of patients and is a very aggressive disease with a grim prognosis. This genetic mutation leads to the production of a mutated growth factor receptor that is always active, causing the cancer cells expressing it to grow uncontrollably. While inhibitors targeting the FLT3 protein specifically are currently being used inThe use of these inhibitors in treating patients at the clinic often leads to relapse.
Funding for this research was provided by Leukaemia Research UK, the Medical Research Council, Blood Cancer Research UK, the Royal Society, the Wellcome, and Cancer Research UK. The lead author, Daniel Coleman, is a John Goldman Fellow of Leukaemia UK.
Â
