Acquired Resistance Mechanisms to Combination Met-TKI/EGFR-TKI Exposure in Met-Amplified EGFR-TKI-Resistant Lung Adenocarcinoma Harboring an Activating EGFR Mutation.
Met-amplified EGFR-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 μmol/L gefitinib for 1 year; three resistant clones were established via Met amplification. The three dual-resistance cell lines (PC-9DR2, PC-9DR4, and PC-9DR6, designated as DR2, DR4, and DR6, respectively) exhibited different mechanisms for evading both EGFR and Met inhibition. None of the clones harbored a secondary mutation of EGFR T790M or a Met mutation. Insulin-like growth factor (IGF)/IGF1 receptor activation in DR2 and DR4 cells acted as a bypass signaling pathway. Met expression was attenuated to a greater extent in DR2 than in PC-9 cells, but was maintained in DR4 cells by overexpression of IGF-binding protein 3. In DR6 cells, Met was further amplified by association with HSP90, which protected Met from degradation and induced SET and MYND domain-containing 3 (SMYD3)-mediated Met transcription. This is the first report describing the acquisition of dual resistance mechanisms in NSCLC harboring an activating EGFR mutation to Met-TKI and EGFR-TKI following previous EGFR-TKI treatment. These results might inform the development of more effective therapeutic strategies for NSCLC treatment. Mol Cancer Ther; 15(12); 3040-54. ©2016 AACR.
Institute of Molecular Oncology, Showa University, Tokyo, Japan. yamaoka.t@med.showa-u.ac.jp.
Toshimitsu
T
Yamaoka
Institute of Molecular Oncology, Showa University, Tokyo, Japan.
Tohru
T
Ohmori
Institute of Molecular Oncology, Showa University, Tokyo, Japan.
Motoi
M
Ohba
Institute of Molecular Oncology, Showa University, Tokyo, Japan.|Center for Biotechnology, Showa University, Tokyo, Japan.
Satoru
S
Arata
Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Yasunari
Y
Kishino
Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Yasunori
Y
Murata
Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Sojiro
S
Kusumoto
Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Hiroo
H
Ishida
Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Takao
T
Shirai
Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Takashi
T
Hirose
Division of Allergology and Respiratory Medicine, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Tsukasa
T
Ohnishi
Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
Yasutsuna
Y
Sasaki
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D000077156:Gefitinib; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D017526:Receptor, IGF Type 1; D053218:Receptors, Death Domain / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; C000597236:IGF1R protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018974:Insulin-Like Growth Factor Binding Protein 4; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D053218:Receptors, Death Domain; D017451:Receptors, Somatomedin; D051899:Smad2 Protein; D051900:Smad3 Protein; D013002:Somatomedins; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D000077156:Gefitinib