Abstract 5594: Targeting ribosomal S6 kinase for the treatment of pediatric acute leukemia

Pediatric acute leukemia accounts for about one third of all childhood cancers. Although the overall survival has improved to 60-70% for pediatric acute myeloid leukemia (AML) and up to 90% for pediatric acute lymphoblastic leukemia (ALL), standard treatments involve intensive chemotherapy and are associated with significant morbidity and mortality. There are few therapies available for relapsed/refractory pediatric acute leukemia. More targeted, less toxic therapies are needed to improve the outcomes for these patients. Ribosomal S6 kinase (RSK) is a serine-threonine kinase activated downstream of the Ras/MAPK signaling pathway and regulates cell proliferation, protein synthesis, and cell survival. RSK activates the transcription factor CREB, which has been found to mediate the proliferation and survival of myeloid cells. RSK is overexpressed and hyperactivated in pediatric AML and associated with a worse prognosis. Here, we evaluated two novel RSK inhibitors for treatment of pediatric AML and ALL. PMD-026 is a specific RSK inhibitor currently in a Phase II clinical trial for adults with metastatic breast cancer. We treated AML cells with a range of doses of PMD-026 and measured the viable cell number after 72 hours. The IC50 of PMD-026 was 298-560nM in Molm13, MV4;11, and Kasumi-1 cells and 1.02-2.24uM in two pediatric AML patient samples. Daunomycin, a standard chemotherapy agent used to treat AML, had synergistic effects when combined with PMD-026 in MV4;11 cells. To evaluate the effects of PMD-026 on normal hematopoietic stem and progenitor cells, we cultured healthy bone marrow mononuclear cells (10^4) with PMD-026 in methylcellulose containing SCF, GM-CSF, IL-3, IL-6, and EPO. Colony formation was not affected up to 10uM for a 17- to 30-fold therapeutic window. The multikinase inhibitor TAS0612 targets RSK, AKT, and S6K and is in Phase I clinical trials for adult solid tumors. In AML cell lines, the IC50 of TAS0612 was between 181-677nM. TAS0612 did not affect normal hematopoietic colony formation up to 1uM. Furthermore, when testing TAS0612 on ALL cell lines, we found that both B-ALL (REH, Nalm-6) and T-ALL cell lines (Loucy, Jurkat) were highly sensitive to TAS0612 with IC50 values of 56-190nM. Healthy T cell proliferation was not affected by TAS0612 up to 5.41uM for a 28- to 97-fold therapeutic window. Further studies are warranted to investigate the roles of RSK and other targets of TAS0612 in ALL. RSK inhibition is a promising approach for the treatment of pediatric acute leukemia. PMD-026 suppresses the proliferation of AML cells and synergizes with chemotherapy. TAS0612 reduces the growth of AML cells and is also effective at targeting B- and T-ALL cells. Both compounds have minimal toxicity to healthy hematopoietic cells. Therefore, PMD-026 and TAS0612 are strong candidates for translation into future clinical trials for AML and ALL. Citation Format: Kailen Mark, Jenny Youm, Ana San Jose Gonzalez, Kathleen M. Sakamoto. Targeting ribosomal S6 kinase for the treatment of pediatric acute 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 5594.