01 Nov AML: Mt. Sinai Researchers Find Link Between RAS Mutations and Treatment Resistance
MedicalResearch.com Interview with:
Dr. Papapetrou
Eirini Papapetrou, MD, PhD
Professor of Oncological Sciences
Professor of Medicine, Hematology and Medical Oncology
Director, Center for Advancement of Blood Cancer Therapies
Co-Director, Stem Cell Engineering Core
Icahn School of Medicine at Mount Sinai
New York, NY 10029
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: RAS in the most commonly mutated oncogene in human cancers. Particularly in acute myeloid leukemia, about one third of cases have RAS mutations. We set out to understand the role of these mutations in the development of leukemia and in response to treatment.
We found that RAS mutations happen late in the course of the disease as progression mutations because they are acquired by more mature leukemic cells coming from preexisting leukemia stem cells (LSCs). Importantly, these more mature cells, upon acquisition of RAS mutations, become leukemia stem cells (LSCs) with different properties than the previous LSCs. Most critically, they develop resistance to a recently FDA-approved drug for the treatment of leukemia, venetoclax (VEN). In addition, these RAS-mutated LSCs give rise to leukemia cells with monocytic differentiation. Both RAS mutations and monocytic differentiation of AML have previously been associated with VEN resistance in clinical studies. We show that it is the RAS mutations that cause both the monocytic differentiation and the VEN resistance. Thus, poor patient outcomes after VEN therapy are driven by RAS mutations and not by monocytic disease.
MedicalResearch.com: What should readers take away from your report?
Response: Both RAS mutations and monocytic differentiation of AML have previously been associated with VEN resistance in clinical studies. We show that it is the RAS mutations that cause both the monocytic differentiation and the VEN resistance. Thus, poor patient outcomes after VEN therapy are driven by RAS mutations and not by monocytic disease.
MedicalResearch.com: What recommendations do you have for future research as a results of this study?
Response: From the perspective of how leukemia and in particular LSCs develop, our study provides a new paradigm: oncogenes transform specific cell types and not others and the properties of LSCs are jointly determined by the oncogene and the cell type. Also, different types of LSCs are present during the course of the cancer and these shift their responsiveness to different therapies, thereby determining clinical responses to therapies. These need to be better understood in order for therapies to be more effective. This paradigm is likely to apply to other leukemia and cancer types. Future studies will likely unveil such cell type-oncogene relationships in other leukemia and cancer cases.
With regards to therapies with venetoclax, specifically, our study shows that RAS mutations are a major cause of resistance and relapse and points to new inhibitor drugs that could be tested, in combination with VEN, in the clinic, in order to overcome resistance.
Citation: Sango, J., Carcamo, S., Sirenko, M. et al. RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax. Nature (2024). https://doi.org/10.1038/s41586-024-08137-x
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Last Updated on November 1, 2024 by Marie Benz MD FAAD