Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms
| Autor: | Chenwei Lin, Anna Reister Schultz, Courtney Follit, Robert H. Collins, Brian J. Druker, Christopher A. Eide, Daelynn R. Buelow, Haijiao Zhang, Yee Ling Lam, Hoang Ho, Hagop M. Kantarjian, Farhad Ravandi, Jorge E. Cortes, Amy S. Carlos, Guillermo Garcia-Manero, Richard S. Sweat, Jeffrey W. Tyner, Vinay K. Jain, Robert P. Searles, Samantha L. Savage, Sharyn D. Baker, Gautam Borthakur, Evan F. Lind, Rachel Henson, Daniel Bottomly, Libbey White, Erik Segerdell, Shannon K. McWeeney, Tamilla Nechiporuk, Beth Wilmot |
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| Přispěvatelé: | Henson, Richard [0000-0002-0712-2639], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Neuroblastoma RAS viral oncogene homolog Male Myeloid General Physics and Astronomy 02 engineering and technology Drug resistance Epigenesis Genetic GTP Phosphohydrolases chemistry.chemical_compound Mice fluids and secretions Piperidines hemic and lymphatic diseases Antineoplastic Combined Chemotherapy Protocols Medicine lcsh:Science Exome sequencing Aged 80 and over Multidisciplinary Myeloid leukemia hemic and immune systems Middle Aged 021001 nanoscience & nanotechnology Isocitrate Dehydrogenase Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Treatment Outcome Tandem Repeat Sequences embryonic structures Female 0210 nano-technology Crenolanib Adult Pyridones Science Pyrimidinones IDH2 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Inhibitory Concentration 50 Cell Line Tumor Exome Sequencing Animals Humans Protein Kinase Inhibitors Aged business.industry Membrane Proteins General Chemistry medicine.disease 030104 developmental biology HEK293 Cells chemistry fms-Like Tyrosine Kinase 3 Drug Resistance Neoplasm Mutation Cancer research lcsh:Q Benzimidazoles Drug Screening Assays Antitumor business |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) |
| ISSN: | 2041-1723 |
| Popis: | FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity. FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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