Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment

Highlights • Met amplification and protein hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR inhibitors • Met inhibition effectively overcomes the resistance to 3rd generation EGFR inhibitors both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle a...

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Veröffentlicht in:	Cancer letters 2016-10, Vol.380 (2), p.494-504
Hauptverfasser:	Shi, Puyu, You, You-Take, Zhang, Guojing, Yao, Weilong, Yue, Ping, Li, Yikun, Kanteti, Rajani, Riehm, Jacob, Salgia, Ravi, Owonikoko, Taofeek K, Ramalingam, Suresh S, Chen, Mingwei, Sun, Shi-Yong
Format:	Artikel
Sprache:	eng
Schlagworte:	Acquisitions & mergers Acrylamides - pharmacology Aniline Compounds - pharmacology Animals Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis Apoptosis - drug effects AZD9291 Bim c-Met protein Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - enzymology Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Cell cycle Cell Line, Tumor Cell Proliferation - drug effects Crizotinib Dose-Response Relationship, Drug Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics EGFR Epidermal growth factor Epidermal growth factor receptors ErbB Receptors - antagonists & inhibitors ErbB Receptors - genetics ErbB Receptors - metabolism Erlotinib Erlotinib Hydrochloride - pharmacology Female G1 Phase Cell Cycle Checkpoints - drug effects Gene Amplification Gene Expression Regulation, Neoplastic Hematology, Oncology and Palliative Medicine Humans Immunoglobulins Kinases Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - pathology Met MET protein Mice, Nude Molecular Targeted Therapy Mutation Non-small cell lung carcinoma Phosphorylation Protein Kinase Inhibitors - pharmacology Protein-tyrosine kinase Proteins Proto-Oncogene Proteins c-met - genetics Proto-Oncogene Proteins c-met - metabolism Pyrazoles - pharmacology Pyridines - pharmacology Pyrimidines - pharmacology Resistance RNA Interference Signal Transduction - drug effects Small cell lung carcinoma Studies Time Factors Transfection Tumor Burden - drug effects Tumors Tyrosine Xenograft Model Antitumor Assays
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Zusammenfassung:	Highlights • Met amplification and protein hyperactivation is a resistance mechanism to both 1st and 3rd generation EGFR inhibitors • Met inhibition effectively overcomes the resistance to 3rd generation EGFR inhibitors both in vitro and in vivo, including enhancement of apoptosis or G1 cell cycle arrest. • Enhanced Bim stabilization is a critical mechanism that mediates augmented induction of apoptosis by combination of Met inhibition with a 3rd generation EGFR inhibitor.
ISSN:	0304-3835 1872-7980
DOI:	10.1016/j.canlet.2016.07.021