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

Koschade, Sebastian E.; Klann, Kevin; Shaid, Shabnam; Vick, Binje; Stratmann, Jan A.; Thölken, Marlyn; Meyer, Laura M.; Duy Nguyen, The; Campe, Julia; Moser, Laura M.; Hock, Susanna; Baker, Fatima; Meyer, Christian T.; Wempe, Frank; Serve, Hubert; Ullrich, Evelyn; Jeremias, Irmela; Muench, Christian and Brandts, Christian H. (2022): Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia. In: Leukemia, Vol. 36, No. 10: pp. 2396-2407

Abstract

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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 0887-6924
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 259130777
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 318346496
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390339347
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 403765277