miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling
Abstract 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 profi...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-07-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708746 |
| _version_ | 1827015178573578240 |
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| author | Cristina Migliore Elena Morando Elena Ghiso Sergio Anastasi Vera P Leoni Maria Apicella Davide Cora' Anna Sapino Filippo Pietrantonio Filippo De Braud Amedeo Columbano Oreste Segatto Silvia Giordano |
| author_facet | Cristina Migliore Elena Morando Elena Ghiso Sergio Anastasi Vera P Leoni Maria Apicella Davide Cora' Anna Sapino Filippo Pietrantonio Filippo De Braud Amedeo Columbano Oreste Segatto Silvia Giordano |
| author_sort | Cristina Migliore |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-07T17:51:22Z |
| format | Article |
| id | doaj.art-f09ddfa6e2014b34a62b8a6110de7ae3 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T14:18:24Z |
| publishDate | 2018-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-f09ddfa6e2014b34a62b8a6110de7ae32024-10-28T08:57:06ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-07-0110911210.15252/emmm.201708746miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signalingCristina Migliore0Elena Morando1Elena Ghiso2Sergio Anastasi3Vera P Leoni4Maria Apicella5Davide Cora'6Anna Sapino7Filippo Pietrantonio8Filippo De Braud9Amedeo Columbano10Oreste Segatto11Silvia Giordano12Department of Oncology, University of TorinoCandiolo Cancer Institute, FPO‐IRCCSCandiolo Cancer Institute, FPO‐IRCCSUnit of Oncogenomics and Epigenetics, IRCCS Regina Elena National Cancer InstituteDepartment of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of CagliariCandiolo Cancer Institute, FPO‐IRCCSDepartment of Oncology, University of TorinoCandiolo Cancer Institute, FPO‐IRCCSMedical Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriMedical Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriDepartment of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of CagliariUnit of Oncogenomics and Epigenetics, IRCCS Regina Elena National Cancer InstituteDepartment of Oncology, University of TorinoAbstract 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.https://doi.org/10.15252/emmm.201708746EGFRERRFI1METresistancetargeted therapy |
| spellingShingle | Cristina Migliore Elena Morando Elena Ghiso Sergio Anastasi Vera P Leoni Maria Apicella Davide Cora' Anna Sapino Filippo Pietrantonio Filippo De Braud Amedeo Columbano Oreste Segatto Silvia Giordano miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling EMBO Molecular Medicine EGFR ERRFI1 MET resistance targeted therapy |
| title | miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling |
| title_full | miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling |
| title_fullStr | miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling |
| title_full_unstemmed | miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling |
| title_short | miR‐205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling |
| title_sort | mir 205 mediates adaptive resistance to met inhibition via errfi1 targeting and raised egfr signaling |
| topic | EGFR ERRFI1 MET resistance targeted therapy |
| url | https://doi.org/10.15252/emmm.201708746 |
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