miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling
| Autor: | Vera Piera Leoni, Maria Apicella, Sergio Anastasi, Elena Morando, Oreste Segatto, Elena Ghiso, Filippo de Braud, Amedeo Columbano, Silvia Giordano, Cristina Migliore, Anna Sapino, Filippo Pietrantonio, Davide Corà |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Medicine (General) medicine.medical_treatment EGFR Drug Resistance Antineoplastic Agents QH426-470 ERRFI1 Targeted therapy resistance 03 medical and health sciences Mediator R5-920 Downregulation and upregulation Crizotinib ErbB Genetics Medicine Humans Pharmacology & Drug Discovery MET targeted therapy Enzyme Inhibitors Receptor Research Articles Adaptor Proteins Signal Transducing Cancer business.industry Sequence Analysis RNA Gene Expression Profiling Tumor Suppressor Proteins Proto-Oncogene Proteins c-met medicine.disease Molecular medicine ErbB Receptors MicroRNAs 030104 developmental biology Cancer research Molecular Medicine Adenocarcinoma business Tyrosine kinase Signal Transduction Research Article |
| Zdroj: | EMBO Molecular Medicine EMBO Molecular Medicine, Vol 10, Iss 9, Pp n/a-n/a (2018) |
| Popis: | The onset of secondary resistance represents a major limitation to long‐term efficacy of target therapies in cancer patients. Thus, the identification of mechanisms mediating secondary resistance is the key to the rational design of therapeutic strategies for resistant patients. MiRNA profiling combined with RNA‐Seq in MET‐addicted cancer cell lines led us to identify the miR‐205/ERRFI1 (ERBB receptor feedback inhibitor‐1) axis as a novel mediator of resistance to MET tyrosine kinase inhibitors (TKIs). In cells resistant to MET‐TKIs, epigenetically induced miR‐205 expression determined the downregulation of ERRFI1 which, in turn, caused EGFR activation, sustaining resistance to MET‐TKIs. Anti‐miR‐205 transduction reverted crizotinib resistance in vivo, while miR‐205 over‐expression rendered wt cells refractory to TKI treatment. Importantly, in the absence of EGFR genetic alterations, miR‐205/ERRFI1‐driven EGFR activation rendered MET‐TKI‐resistant cells sensitive to combined MET/EGFR inhibition. As a proof of concept of the clinical relevance of this new mechanism of adaptive resistance, we report that a patient with a MET ‐amplified lung adenocarcinoma displayed deregulation of the miR‐205/ERRFI1 axis in concomitance with onset of clinical resistance to anti‐MET therapy. |
| Databáze: | OpenAIRE |
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