miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling

EMBO Molecular Medicine
Cristina MiglioreSilvia Giordano

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...Continue Reading

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Citations

Oct 16, 2019·Frontiers in Oncology·Roberta RoncaratiMassimo Negrini
Nov 9, 2018·International Journal of Molecular Sciences·Toshimitsu YamaokaTohru Ohmori
Sep 19, 2019·Cancers·Yoojung KwonDooil Jeoung
May 22, 2020·Frontiers in Cell and Developmental Biology·Xing HuangTingbo Liang
Apr 23, 2020·International Journal of Molecular Sciences·Ruben Mercado SantosWen Cai Zhang
Nov 17, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Ana Bela Sarmento-RibeiroIoannis P Trougakos
Dec 1, 2020·Translational Research : the Journal of Laboratory and Clinical Medicine·Shen ZhongJürgen Borlak
Mar 12, 2021·Frontiers in Cell and Developmental Biology·Lixian LiuXuri Li
Jul 6, 2021·The World Allergy Organization Journal·Chang-Yu QiuLei Cheng
Jan 26, 2022·Molecular Biology Reports·Swagata RoySatarupa Banerjee

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Datasets Mentioned

BETA
GSE114406
PRJNA451125

Methods Mentioned

BETA
PCR
transfection
biopsy
biopsies
Assay
electrophoresis
Low Density Arrays

Clinical Trials Mentioned

NCT02414139
NCT01610336

Software Mentioned

Bowtie
ImageJ
TargetScan
Leica Assistant Suit ( LAS EZ )
GraphPad Prism
RSEM
EBseqtool
Ensembl
GENECODE
GEDAS

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