Investigating the Determinants of Response to Pan-RAS Inhibition in Juvenile Myelomonocytic Leukemia

About This Grant

PROJECT SUMMARY Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm that typically affects infants and toddlers. In contrast to most hematologic malignancies where RAS mutations represent late events, we and others have shown that nearly all JMML patients have initiating mutations in the RAS pathway. In the majority of patients, this is the only oncogenic mutation found in the genome. This suggests a potential opportunity to treat this disease with targeted inhibitors of RAS signaling. Indeed, we previously found that MEK inhibition (MEKi) alleviates disease in mouse models of JMML and translated this to a recently completed Phase 2 trial (NCT03190915) in children with relapsed/refractory JMML demonstrating clinical benefit of MEKi. However, only half of all patients responded, and none demonstrated molecular responses, defined by reductions in the mutant allele burden of the founding RAS mutations. We have since shown that additional RAS effector pathways (PI3K, mTOR, AKT) in addition to RAF/MEK/ERK (MAP kinase) sustain growth upon MEKi. These findings potentially explain the variable responses to MEKi observed in patients. To address these concerns, we have tested the best-in-class Pan-RAS inhibitor RMC-7977, developed by Revolution Medicines. This compound is a “molecular glue” that binds to all active RAS proteins (i.e., only in the GTP-bound state), and recruits a second protein, cyclophilin A, to sterically prevent active RAS from reaching its effectors. We have now tested RMC-7977 in primary samples from patients with JMML and in patient derived xenograft (PDX) models of JMML and acute myeloid leukemia (AML) with RAS mutations and have observed remarkable efficacy. However, the mechanisms of response and resistance to direct RAS inhibition (RASi) have not been elucidated in hematologic malignancies. We hypothesize that specific RAS genotypes including NRAS and KRAS will be more sensitive to RMC-7977 than other RAS family members including PTPN11 and NF1. We also hypothesize that the “dosage” of RAS mutations will impact sensitivity to the drug. Lastly, we hypothesize that the cell of origin in which RAS mutations arise will impact sensitivity to RASi. We will test these hypotheses using rare primary samples, PDXs and induced pluripotent stem cells. Because primary samples from infants with JMML are difficult to obtain, determinants of response to RASi cannot be adequately modeled in-vitro alone. The proposed studies will use PDX models to evaluate therapeutic efficacy, characterize mechanisms of response and resistance, and validate findings in the context of an intact hematopoietic microenvironment. These animal studies are essential for translating mechanistic discoveries into future clinical trials for children with JMML. While rare, JMML represents a genomically “simple” disease to study Pan-RAS inhibition. The results can then be applied to more common and genomically “complex” diseases like acute myeloid leukemia and myeloproliferative neoplasms that harbor RAS mutations.