Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research
Methods: We conducted both in vitro and in vivo experiments. For in vitro experiments, we used the human B-precursor ALL cell lines MUTZ5 and MHH-CALL-4 as well as patient derived Ph-like ALL cells that carry CRLF2 translocation. We used flow cytometry techniques to measure cell viability. Western blotting analysis was used to quantify pro-survival and pro-apoptotic proteins in the treated cell lines. For in vivo experiments, we used mouse patient-derived xenograft (PDX) model in which NSG mice were injected with patient derived Ph-like ALL cells.
Results: In vitro experiments confirmed that the type II JAK inhibitor CHZ-868 had more potent cytotoxic effects than ruxolitinib in CRLF2-r cell lines and cells derived from PDX models. Short-term starvation with low glucose and low serum strongly sensitized CRLF2-r cell lines to CHZ-868 cytotoxicity. Mechanistically, the combination of CHZ-868 and starvation was associated with decreased expression of the pro-survival protein MCL-1 and increased expression of the pro-apoptotic protein BIM. In vivo experiments using a CRLF2-r PDX model showed that FMD reduced leukemic burden and enhanced the efficacy of CHZ-868.
Conclusion: Efficacy of the type II JAK inhibitor CHZ-868 in CRLF2-r cells is enhanced by nutrient restriction. These results provide proof-of-concept for testing FMD as a diet-based approach to enhance TKI efficacy in Ph-like B-ALL patients.
Disclosures: Huynh: Servier: Research Funding. Tasian: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Incyte Corporation: Research Funding; Wugen, Inc: Membership on an entity's Board of Directors or advisory committees; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Amgen: Other: Travel support; AstraZeneca: Membership on an entity's Board of Directors or advisory committees.
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