The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.

Autor: Villaume MT; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN., Arrate MP; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN., Ramsey HE; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN., Sunthankar KI; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN., Jenkins MT; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN., Moyo TK; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN., Smith BN; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN; Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN., Fischer MA; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN., Childress MA; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN., Gorska AE; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN., Ferrell PB; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN; Center for Immunobiology, Vanderbilt University School of Medicine, Nashville, TN; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN., Savona MR; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN; Center for Immunobiology, Vanderbilt University School of Medicine, Nashville, TN; Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN. Electronic address: michael.savona@vanderbilt.edu.
Jazyk: angličtina
Zdroj: Experimental hematology [Exp Hematol] 2021 May; Vol. 97, pp. 57-65.e5. Date of Electronic Publication: 2021 Feb 19.
DOI: 10.1016/j.exphem.2021.02.008
Abstrakt: 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.)
Databáze: MEDLINE
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