Use of the novel menin inhibitor revumenib has led to remissions in patients with acute myeloid leukemia (AML), and associated findings have suggested the mechanisms through which cancer cells may become resistant to such treatment, according to two studies published by Issa et al and Perner et al, respectively, in Nature.
Findings from the first study demonstrated that approximately 40% of patients with acute leukemia subtypes had a complete response to revumenib. Findings from the second study uncovered a molecular countermove through which acute leukemia cells may evade the drug and reassert their growth.
Both of the new studies highlight the promise of the targeted approach to treating acute leukemia exemplified by revumenib and the potential to extend its benefits with medications that inhibit the resistance mechanism.
Background
"The two genetic subtypes of acute leukemia involved in this research account for approximately 40% of all cases of AML in [pediatric] and adult [patients]," explained the second study’s co–senior study author Scott Armstrong, MD, PhD, the David G. Nathan Professor of Pediatrics at Harvard Medical School, Associate Chief of the Division of Hematology/Oncology at Boston Children’s Hospital, Chairman of the Department of Pediatric Oncology at Dana-Farber Cancer Institute, and President of the Dana-Farber Cancer Institute/Boston Children’s Hospital Cancer and Blood Disorders Center. "They're driven by a rearrangement of the MLL1 gene or a mutation in the NPM1 gene. Both types depend on a protein called menin to sustain their growth,” he added.
Menin is a critical part of the cell's epigenetic mechanism for switching gene activity on and off. As a scaffolding protein, it binds to chromatin and summons large protein complexes to join it. The complexes tighten or loosen the coils of DNA, changing the activity level of the genes at that site. One of the key proteins within these complexes is MLL1—the product of the MLL1 gene.
Methods and Results of the Revumenib Studies
In the first study—involving the results of the phase I/II clinical AUGMENT-101 trial—researchers tested the efficacy of revumenib at targeting menin in 68 patients with acute leukemia who didn’t respond to previous therapies. Among the 60 patients who could be evaluated, 53% (n = 32) of them responded to the drug and 30% (n = 18) had a complete response.
"For patients with acute leukemia who have undergone several previous treatments, this is a very encouraging result. However, after the second cycle of treatment, some patients did develop resistance to revumenib,” stressed Dr. Armstrong.
In the second study—a follow-up of the first study—Dr. Armstrong and his colleagues sought a source of that resistance.
"Revumenib contains a small molecule that inhibits the interaction of menin and MLL1. The AUGMENT trial shows it can produce remissions in a high percentage of patients,” emphasized Dr. Armstrong.
When the researchers analyzed bone marrow samples from some of the patients who became resistant to revumenib, they found that many of them had developed MEN1 mutations, resulting in the development of the menin protein. The mutation possibly leads to a deformed version of menin that doesn't bind well to revumenib but is still capable of attaching to MLL1. As menin and MLL1 renew their interaction, the leukemia cells begin to grow again.
Conclusions
Dr. Armstrong underscored that the new findings provide “formal proof in patients that menin itself is a valid target for therapy in both genetic subtypes of AML.”
He explained: “The fact that the cell has gone through so much trouble to mutate MEN1 in order to survive is a strong indication that we’re hitting a target the cell truly relies on. The ability of revumenib to stress leukemia cells to the point where they develop a mutation to remain alive may be a testament to the drug’s effectiveness. This is the first time a drug targeting a chromatin-binding protein complex has been shown to put that degree of pressure on cancer in a human patient.”
By tracking the development of MEN1 mutations and other genes in patients with acute leukemia, the researchers may be able to identify patients at high risk of relapsing who may benefit from further treatment. The discovery of the MEN1 mutation as a resistance mechanism suggests that new drugs specifically targeting menin or other chromatin-associated proteins could prevent or delay revumenib resistance—or treat patients who have already become resistant to the drug.
“Seeing Dr. Armstrong’s work translated elegantly into the clinic where patients—including some … who had dramatic responses in dire situations—was highly gratifying personally and professionally,” noted study author Richard Stone, MD, Professor of Medicine at Harvard Medical School, as well as Chief of Staff, Director of Translational Research in the Adult Leukemia Program, and the Lunder Family Chair in Leukemia at Dana-Farber Cancer Institute. “We are now ready to magnify the impact of these results by conducting clinical trials combining revumenib with standard chemotherapy as well as with novel agents, also based on preclinical work done in great part by Dr. Armstrong,” he concluded.
Disclosure: For full disclosures of the study authors visit nature.com and nature.com.
