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Pim kinases modulate resistance to tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia

Green, Alexa/S and Maciel, Thiago/T and Hospital, Marie-Anne and Yin, Chae and Townsend, Elizabeth/C and Pilorge, Sylvain and Jacquel, Arnaud and Lambert, Mireille and Paubelle, Etienne and Zylbersztejn, Florence and Decroocq, Justine and Kosmider, Olivier and Auberger, Patrick and Hermine, Olivier and Weinstock, David/M and Lacombe, Catherine and Mayeux , P and Vanasse, K. Gary and Leung, Anscar Y and Moura, IC and Bouscary, Didier and Tamburini, Jerome (2015) Pim kinases modulate resistance to tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia. Science Advances, 1 (8). e1500221. ISSN 2375-2548

Abstract

Fms-related tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are
frequently detected in acute myeloid leukemia (AML) patients and are associated with a
dismal long-term prognosis. FLT3 tyrosine kinase inhibitors (TKI) may provide efficient
short-term disease control, however virtually all responding patients relapse within few
months. The oncogenic Pim protein kinases are FLT3 targets expressed in AML cells but their
participation in disease pathogenesis is incompletely understood. Here we show that Pim-2
overexpression is frequently found in samples from AML patients experiencing resistance to
TKI therapy. Pim-2 activity is critical for tumor propagation in TKI-resistant cells and in a
mouse model of FLT3-ITD-induced myeloproliferative neoplasm ectopic Pim-2 expression
induces TKI resistance. Inhibition of Pim kinases enhances TKI docking on FLT3 ATPbinding
pocket therefore restoring its ability to block downstream receptor signaling. Finally,
combined Pim and FLT3 kinases inhibitors efficiently eradicate FLT3-mutated cell lines and
primary AML samples. The implication of Pim kinases in TKI resistance open new
perspectives for AML targeted therapies.

Item Type: Article
Keywords: AC220 (quizartinib), LGB321, FLT3-ITD, AML, Pim kinases
Date Deposited: 29 Apr 2016 23:45
Last Modified: 29 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/22678

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