GSE114406 ERRFI1 targeting by miR-205 mediates adaptive resistance to MET inhibition through enhanced EGFR signaling

Contributors : Cristina Migliore ; D Cor à ; Silvia GiordanoSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensThe 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 key to the rational design of alternative therapeutic strategies for resistant patients. MiRNA profiling combined with RNA-seq in MET-addicted gastric and lung 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, increased miR-205 expression determined the downregulation of the EGFR inhibitor ERRFI1, which, in turn, caused EGFR activation and MET-TKI resistance. 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 newly identified 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 the onset of clinical resistance to anti-MET therapy.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research