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MET amplification increases the metastatic spread of EGFR-mutated NSCLC.
- Source :
-
Lung cancer (Amsterdam, Netherlands) [Lung Cancer] 2018 Nov; Vol. 125, pp. 57-67. Date of Electronic Publication: 2018 Sep 11. - Publication Year :
- 2018
-
Abstract
- Background: Five to 20% of metastatic EGFR-mutated non-small cell lung cancers (NSCLC) develop acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) through MET amplification. The effects of MET amplification on tumor and patient phenotype remain unknown.<br />Methods: We investigated,in vitro and in vivo, the impact of MET amplification on the biological properties of the HCC827 cell line, derived from an EGFR-mutated NSCLC. We further evaluated the time to new metastases after EGFR-TKI progression in EGFR-mutated NSCLC, exhibiting MET amplification or high MET overexpression.<br />Results: MET amplification significantly enhanced proliferation, anchorage independent growth, anoikis resistance, migration, and induced an epithelial to mesenchymal transition. In vivo, MET amplification significantly increased the tumor growth and metastatic spread. Treatment with a MET-TKI reversed this aggressive phenotype. We found that EGFR-mutated NSCLC patients exhibiting MET amplification on a re-biopsy, performed after EGFR-TKI progression, displayed a shorter time to new metastases after EGFR-TKI progression than patients with high MET overexpression but no MET amplification.<br />Conclusion: MET amplification increases metastatic spread even in the context of an already pre-existing strong driver mutation such as EGFR mutation. These results prompt development of therapeutic strategies aiming at preventing emergence of MET amplification.<br /> (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Movement genetics
Cell Proliferation genetics
Drug Resistance, Neoplasm genetics
ErbB Receptors genetics
Humans
Mice
Mice, SCID
Mutation genetics
Neoplasm Metastasis pathology
Protein Kinase Inhibitors therapeutic use
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Gene Amplification genetics
Lung Neoplasms genetics
Neoplasm Metastasis genetics
Proto-Oncogene Proteins c-met genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1872-8332
- Volume :
- 125
- Database :
- MEDLINE
- Journal :
- Lung cancer (Amsterdam, Netherlands)
- Publication Type :
- Academic Journal
- Accession number :
- 30429039
- Full Text :
- https://doi.org/10.1016/j.lungcan.2018.09.008