Relapses in acute myeloid leukemia (AML) can be prevented through new research that has identified how cancer develops resistance to first-line treatments. 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 found that mutated AML samples from patients who relapsed after receiving FLT3 inhibitor treatment had up-regulated multiple signaling pathways to overcome the drug’s action. By targeting RAS family proteins with a small molecule inhibitor developed from a chemical library screen, signaling that rescued the cells from death could be prevented.
The resistant cancer’s genetic changes were able to be replicated in lab tests, showing that transcription factors AP-1 and RUNX1 were crucial in mediating drug resistance. The drugs targeting FLT3 rewired the cell, resulting in the upregulation of other signaling pathway-associated genes, which then restored AP-1 and RUNX1 binding. Drugging RAS, a key component in multiple signaling pathways, prevented the restoration of RUNX1 binding, ultimately preventing the cancer cells from escaping cell death. This discovery sheds light on how cancer cells can adapt and overcome the effects of targeted therapies by utilizing different signaling pathways.
Professor Constanze Bonifer, one of the senior authors of the study, emphasized the importance of targeting RAS family members to prevent cancer cells from rewiring and using different signaling pathways to escape cell death. The small molecule inhibitors used to target RAS in the study were developed using intracellular antibody technology, which involves screening antibody fragments to identify those that bind to the target protein in cells and prevent their protein-protein interactions. This Antibody-derived technology allows for the development of drugs to target difficult-to-drug proteins and identify new parts of the protein that can be targeted to prevent protein-protein interactions.
AML with a FLT3-ITD mutation, which occurs in nearly 30% of all patients, is a highly aggressive disease with a poor prognosis. While inhibitors targeting the FLT3 protein are in use in the clinic, patients treated with these inhibitors often relapse. The research was funded by various organizations, including Leukaemia Research UK, the Medical Research Council, Blood Cancer Research UK, the Royal Society, the Wellcome Trust, and Cancer Research UK. The development of new generation drugs using Abd technology to target hard-to-drug proteins may lead to improved treatment options for patients with relapsed AML.
In conclusion, the study highlights the significance of identifying and targeting key signaling pathways involved in drug resistance in AML. By understanding how cancer cells adapt to targeted therapies and developing inhibitors to prevent these adaptations, researchers have made progress in potentially preventing relapse in leukemia patients. The use of small molecule inhibitors developed through intracellular antibody technology offers a promising approach to target difficult-to-drug proteins and improve outcomes for patients with aggressive malignancies like AML. Future research in this area may lead to the development of more effective and personalized treatment strategies for patients with relapsed AML and other cancers.
