Project Term
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Dana-Farber Cancer Institute
Boston, MA
United States
Project Summary
Menin inhibitors are a new type of targeted cancer drug designed to block an abnormal protein complex called Menin, KMT2A, and LEDGF, which drives certain genetic forms of acute myeloid leukemia (AML). These drugs can switch off leukemia-causing genes, but by themselves they rarely lead to a cure, and some leukemias develop resistance through mutations in the MEN1 gene that prevent the drug from working properly. Our research has now uncovered additional mutations in MEN1, KMT2A, and LEDGF, genes that help form the same complex, that make leukemia cells resistant in new ways. We believe these changes strengthen the complex’s grip on DNA and blunt the effect of Menin inhibitors. In this project, we aim to understand exactly how these mutations cause resistance and to explore new combination treatments that could make Menin inhibitors more effective for patients with AML.
Lay Abstract
Acute myeloid leukemia (AML) is a difficult blood cancer to treat. Certain types of AML, such as KMT2A-rearranged (KMT2A-r) and NPM1-mutant (NPM1c) AML, rely on a specific protein interaction (KMT2A-Menin-LEDGF) to drive cancer genes and growth. Blocking this interaction with drugs called Menin inhibitors has shown promise in reversing cancer-related gene activity, shrinking tumors, and improving survival in lab studies. In a clinical trial that tested a Menin inhibitor called revumenib in patients with hard-to-treat AML, about 20-30% of patients achieved complete remission, leading to FDA approval of revumenib in 2024.
However, some patients stop responding to Menin inhibitors due to changes, called mutations, in the MEN1, KMT2A or LEDGF genes. We are studying these mutations and how they affect Menin inhibitors, as well as looking at combining Menin inhibitors with other drugs to overcome this resistance. We want to explore how these mutations affect drug activity and protein interactions between Menin and KMT2A. We will also look to see how mutations change cancer-related gene activity. We also want to look at combining Menin inhibitors with other drugs to see if they work better together and can overcome resistance caused by mutations. Understanding these mutations will help us create better treatment plans and develop new drug combinations that work even when these changes occur.
Program