MEN1 Mutations Induce Acquired Resistance to the Menin Inhibitor Revumenib

KMT2A gene rearrangements (KMT2Ar) occur in 5 to 10% of patients with acute leukemia and in up to 70 to 80% of infant leukemia cases.^1–3 KMT2A binds to a co-factor called menin, which is required for the complex to bind to chromatin, and induces the aberrant overexpression of HOX genes.^4,5  Several clinical trials have begun to investigate the value of small-molecule inhibitors targeting menin in patients with KMT2Ar leukemias and in those with NPM1 mutations. Results from the phase I portion of the AUGMENT-101 trial (NCT04065399), a study evaluating the menin inhibitor revumenib (SNDX-5613), were recently published.⁶  The study included 68 patients with relapsed or refractory acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or mixed-phenotype acute leukemia. The protocol was amended early on to include only patients with a KMT2Ar or NPM1 mutation; in these patients, the overall response rate was 53% (n=32/60), with a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 30% (n=18/60).⁶  The most common treatment-related adverse events included QTc prolongation (52.9%), nausea (26.5%), and differentiation syndrome (16.2%).⁶  The phase II portion of AUGMENT-101 is ongoing.

To assess the mechanisms underlying acquired resistance to revumenib, Dr. Florian Perner and colleagues studied samples collected from AUGMENT-101 participants. First, they performed targeted sequencing on bone marrow samples collected from four patients (three with KMT2Ar and one with an NPM1 mutation) whose disease initially responded to revumenib and subsequently progressed. All four patients had one or more mutations in the MEN1 gene at the time of progression. MEN1 residues affected included M327, T349, G331, and S160. Next, they assessed the frequency of MEN1 mutations in 31 samples from responders and non-responders collected prior to treatment with revumenib and after at least two cycles of revumenib. While MEN1 mutations were not detected in any samples prior to revumenib treatment, MEN1 mutations were found in 12 of 31 patients (38.7%) after revumenib treatment. In some patients, the MEN1 mutations were detected prior to overt morphologic relapse.

The authors then performed a series of experiments to confirm that the MEN1 mutations observed in the clinical samples caused resistance to menin inhibition. Patient-derived xenograft (PDX) mouse models with KMT2Ar or NPM1 mutations were treated with the menin inhibitor VTP-50469, and acquired MEN1 mutations were identified at the time of disease relapse in 15 of 22 mice (68%). A CRISPR-Cas9 base-editor screen in two KMT2Ar cell lines that had been treated with VTP-50469 also identified MEN1 mutations as mediators of resistance to VTP-50469. Many of the same amino acid residues in MEN1 that had been identified in the clinical samples were also detected in the PDX models and in the CRISPR-Cas9 base-editor screen. Crystallography and computational methods revealed that the MEN1 mutations identified affect the binding pocket of the protein.