Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia

KMT2A-rearranged acute leukemias are especially prevalent in the pediatric population. The KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are common in pediatric leukemia. In a cohort of 1605 patients enrolled on Children’s Oncology Group (COG) trials AAML0531 and AAML1031, we identified RAS pathway mutations in 43% of AML cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with lower complete remission (CR) rate, poor event-free survival (EFS) and early relapses. We next sought to identify efficacious targeted drug combinations for this subset of childhood leukemia. We evaluated the combination of RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib with the menin inhibitor revumenib. Treatment of acute leukemia cell lines and cultured leukemia cells from patient-derived xenograft (PDX) models resulted in a synergistic decrease in viability, promoted cell cycle arrest, and promoted downregulation of targets of MYC signaling by each drug alone and even more effectively with the combination. In vivo, the combination treatment of AML and ALL pediatric PDX models harboring KMT2A-r and RAS mutations reduced leukemia burden effectively compared with the single drug-treated cohorts. Tissues from treated mice showed a decrease in protein levels of MYC, P-ERK and MEIS1, highlighting effective target engagement of the drugs. Our preclinical study suggests a promising, readily translatable targeted treatment for KMT2A-r RAS pathway mutant leukemias.