1. The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.
- Author
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Villaume MT, Arrate MP, Ramsey HE, Sunthankar KI, Jenkins MT, Moyo TK, Smith BN, Fischer MA, Childress MA, Gorska AE, Ferrell PB, and Savona MR
- Subjects
- Cell Line, Tumor, Cell Survival drug effects, Class I Phosphatidylinositol 3-Kinases metabolism, Drug Synergism, Humans, Leukemia, Myelomonocytic, Chronic enzymology, Molecular Targeted Therapy, Nitriles, Pyrimidines, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Heterocyclic Compounds, 4 or More Rings pharmacology, Leukemia, Myelomonocytic, Chronic drug therapy, Phosphoinositide-3 Kinase Inhibitors pharmacology, Pyrazoles pharmacology
- Abstract
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms, and propensity for transformation to acute myeloid leukemia (AML), with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the phosphatidylinositol-3-kinase (PI3K)-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD:PIK3CA ratio in monocytic M5 AML patients and cell lines, and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro. Because CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor umbralisib as a single agent and in combination with the JAK1/2 inhibitor ruxolitinib, in CMML. Our ex vivo experiments with primary CMML patient samples revealed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT, and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data indicate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation., Competing Interests: Conflict of interest disclosure MRS receives research funding from Astex, Incyte, Millennium, and TG Therapeutics; serves on consultancy/advisory board/monitoring committees for AbbVie, Astex, BMS, Celgene, Geron, Karyopharm, Millennium, Ryvu, Sunesis, and TG Therapeutics; has equity in Karyopharm; and has patents and royalties with Boehringer-Ingelheim. The remaining authors have no competing financial interests., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2021
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