Researchers have provided new insights into acute myeloid leukemia (AML) and its resistance to venetoclax, according to a recent study published by Sango et al in Nature.
Although AML is a rare disease, approximately 20,800 U.S. patients will be diagnosed in 2024, according to the American Cancer Society. RAS genes—including KRAS, HRAS, and NRAS—are frequently mutated in AML, and these mutations typically appear later in the disease. They specifically target certain blood cell types, making them more aggressive and harder to treat.
Study Methods and Results
In the study, the researchers used genetically engineered models and patient-derived cells, combined with advanced genomic technologies, to investigate the role of RAS mutations in AML and their impact on drug response. They found that RAS mutations specifically targeted granulocyte-monocyte progenitors that have already acquired early mutations, transforming them into RAS-mutant leukemia stem cells. This process leads to leukemias with distinct characteristics, including resistance to venetoclax, which is caused by changes in proteins that control apoptosis impacted by RAS mutations.
“We discovered that these RAS-mutant leukemia stem cells behave differently from other leukemia stem cells,” emphasized senior study author Eirini Papapetrou, MD, PhD, Professor of Oncological Sciences at the Icahn School of Medicine at Mount Sinai, New York. “This could explain why some patients do not respond well to the widely used drug venetoclax, which the [U.S.] Food and Drug Administration approved for AML treatment in October 2020,” she added.
Conclusions
The findings highlighted the importance of personalized medicine, where treatments are tailored to the specific genetic characteristics of each patient’s cancer. This approach could lead to better outcomes and improved quality of life among those with AML.
“This study has implications for patients with RAS mutations. It suggests that treatment with venetoclax might not be effective for these individuals and could even worsen their condition. For these patients, providers should consider a combination of therapies that include new RAS inhibitors, which could improve treatment results,” Dr. Papapetrou underscored. “Our study supports the rationale of testing combinations of venetoclax with RAS inhibitors as well as MCL-1 and/or BCL-xL inhibitors. Such inhibitors are currently at different stages of preclinical and clinical development and, based on our results, could be tested in combination with venetoclax in patients with AML with RAS mutations,” she concluded.
Disclosure: The research in this study was supported by the National Institutes of Health and various philanthropic foundations. For full disclosures of the study authors, visit nature.com.
