PP2A-activating Drugs Enhance FLT3 Inhibitor Efficacy through AKT Inhibition–Dependent GSK-3β–Mediated c-Myc and Pim-1 Proteasomal Degradation
Year: 2021
Type: article
Abstract: Fms-like tyrosine-like kinase 3 internal tandem duplication (FLT3-ITD) is present in acute myeloid leukemia (AML) in 30% of patients and is associated with short disease-free survival. FLT3 inhibitor efficacy is limited and transient but may be enhanced by multitargeting of FLT3-ITD signaling pathways. FLT3-ITD drives both STAT5-dependent transcription of oncogenic Pim-1 kinase and inactivation of the tumor-suppressor protein phosphatase 2A (PP2A), and FLT3-ITD, Pim-1, and PP2A all regulate the c-Myc oncogene. We studied mechanisms of action of cotreatment of FLT3-ITD–expressing cells with FLT3 inhibitors and PP2A-activating drugs (PADs), which are in development. PADs, including FTY720 and DT-061, enhanced FLT3 inhibitor growth suppression and apoptosis induction in FLT3-ITD–expressing cell lines and primary AML cells in vitro and MV4-11 growth suppression in vivo. PAD and FLT3 inhibitor cotreatment independently downregulated c-Myc and Pim-1 protein through enhanced proteasomal degradation. c-Myc and Pim-1 downregulation was preceded by AKT inactivation, did not occur in cells expressing myristoylated (constitutively active) AKT1, and could be induced by AKT inhibition. AKT inactivation resulted in activation of GSK-3β, and GSK-3β inhibition blocked downregulation of both c-Myc and Pim-1 by PAD and FLT3 inhibitor cotreatment. GSK-3β activation increased c-Myc proteasomal degradation through c-Myc phosphorylation on T58; infection with c-Myc with T58A substitution, preventing phosphorylation, blocked downregulation of c-Myc by PAD and FLT3 inhibitor cotreatment. GSK-3β also phosphorylated Pim-1L/Pim-1S on S95/S4. Thus, PADs enhance efficacy of FLT3 inhibitors in FLT3-ITD–expressing cells through a novel mechanism involving AKT inhibition–dependent GSK-3β–mediated increased c-Myc and Pim-1 proteasomal degradation.
Source: Molecular Cancer Therapeutics
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, U.S. Department of Veterans Affairs, New York City Department of Health and Mental Hygiene, Maryland Department of Health and Mental Hygiene, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: Small Molecule Activators of PP2A (SMAPs) for Prostate Cancer Therapy, Role of Protein Phosphatase 2A in Aortic Aneurysm, Structural and molecular determinants of protein phosphatase 2A function in lung cancer, G3882229883, Role of microRNAs in the regulation of CML stem cell self renewal and survival, G4119534169, G4175319795, G4804889694, G5850682332, G6722274703, Expanding Participation by Minorities in Biomedical Sciences, G8270953580, UNIVERSITY OF MARYLAND GREENEBAUM CANCER CENTERSUPPORT GRANT
OpenAlex ID: W3126783114