Abstract 7219: Targeting the RAS pathway with MEK and pan-RAF inhibition in Philadelphia-like acute lymphoblastic leukemia

Abstract Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) afflicts close to 30% of adolescents and young adults with ALL and portends a poor response to standard chemotherapy. Ph-like ALL often harbors CRLF2-rearrangements (CRFL2-R) and JAK2 mutations. CRLF2-R and JAK2 can further activate RAS signaling with or without RAS pathway mutations, suggesting a role to target this pathway in Ph-like ALL. Here, we report our results using a novel combination of the MEK inhibitor trametinib (tram) and the pan-RAF inhibitor tovorafenib (tovo) in a CRLF2-R ALL patient-derived xenograft. We identified a CRLF2-R ALL sample from our institution’s biorepository. The sample had an IGH-R by cytogenetics, CRLF2 overexpression by flow cytometry, and JAK2 by NGS. The sample was injected into immunodeficient (NSG) mice. Peripheral blood flow cytometry for human CD19 and human CD45 vs mouse CD45 expression was monitored. Following engraftment >20%, mice were sacrificed and mononuclear cells isolated from the spleen were exposed to drugs to assess in vitro response. In vivo response was then tested in cohorts of 5 mice injected per condition. Upon engraftment, cohorts were treated with vehicle, 1mg/kg/day tram, 12.5mg/kg/day tovo, or the combination daily until moribund. CRLF2-R ALL cells showed in vitro sensitivity to tram as assessed by viability and phosphorylation of ERK at low nM concentrations. These cells showed minimal response to tovo at µM concentrations. Combination with tram and tovo did not show added benefit. Upon injection, mice engrafted within 1 month and rapidly succumbed to disease. In vivo treatment with single agent or combinations briefly, but significantly improved survival compared to control (Table 1). Targeting the RAS pathway in CRLF2-R ALL has therapeutic potential. Interestingly, addition of the pan-RAF inhibitor tovorafenib to trametinib did not have further therapeutic benefit. These findings begin to shed insight into novel targets for CRLF2-R ALL. Citation Format: Hong A. De Sa, Isabel Kenna, Jeffrey W. Tyner, Bill H. Chang. Targeting the RAS pathway with MEK and pan-RAF inhibition in Philadelphia-like acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7219.