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Koschade, S.E.* ; Klann, K.* ; Shaid, S.* ; Vick, B. ; Stratmann, J.A.* ; Thölken, M.* ; Meyer, L.M.* ; Nguyen, T.D.* ; Campe, J.* ; Moser, L.M.* ; Hock, S.* ; Baker, F.* ; Meyer, C.T.* ; Wempe, F.* ; Serve, H.* ; Ullrich, E.* ; Jeremias, I. ; Münch, C.* ; Brandts, C.H.*

Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia.

Leukemia 36, 2396-2407 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25 % of acute myeloid leukemia (AML) patients, drive leukemia progression and confer a poor prognosis. Primary resistance to FLT3 kinase inhibitors (FLT3i) quizartinib, crenolanib and gilteritinib is a frequent clinical challenge and occurs in the absence of identifiable genetic causes. This suggests that adaptive cellular mechanisms mediate primary resistance to on-target FLT3i therapy. Here, we systematically investigated acute cellular responses to on-target therapy with multiple FLT3i in FLT3-ITD + AML using recently developed functional translatome proteomics (measuring changes in the nascent proteome) with phosphoproteomics. This pinpointed AKT-mTORC1-ULK1-dependent autophagy as a dominant resistance mechanism to on-target FLT3i therapy. FLT3i induced autophagy in a concentration- and time-dependent manner specifically in FLT3-ITD + cells in vitro and in primary human AML cells ex vivo. Pharmacological or genetic inhibition of autophagy increased the sensitivity to FLT3-targeted therapy in cell lines, patient-derived xenografts and primary AML cells ex vivo. In mice xenografted with FLT3-ITD + AML cells, co-treatment with oral FLT3 and autophagy inhibitors synergistically impaired leukemia progression and extended overall survival. Our findings identify a molecular mechanism responsible for primary FLT3i treatment resistance and demonstrate the pre-clinical efficacy of a rational combination treatment strategy targeting both FLT3 and autophagy induction.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 36, Issue: 10, Pages: 2396-2407 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Grants Deutsche Forschungsgemeinschaft (German Research Foundation)