Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells

被引:85
作者
Agarwal, S. [1 ,2 ]
Zerillo, C. [2 ]
Kolmakova, J. [1 ]
Christensen, J. G. [3 ]
Harris, L. N. [2 ]
Rimm, D. L. [1 ]
DiGiovanna, M. P. [2 ]
Stern, D. F. [1 ]
机构
[1] Yale Univ, Dept Pathol, Sch Med, New Haven, CT 06520 USA
[2] Yale Univ, Dept Internal Med, Sect Med Oncol, Yale Comprehens Canc Ctr,Sch Med, New Haven, CT 06520 USA
[3] Pfizer Global Res & Dev, Dept Res Pharmacol, La Jolla, CA 92121 USA
关键词
Met; Her/ErbB receptor family; lung cancer; signal transduction; RTK; C-MET; TYROSINE KINASE; GEFITINIB RESISTANCE; ACQUIRED-RESISTANCE; T790M MUTATIONS; EGFR MUTATIONS; TUMOR-CELLS; PATHWAYS; OVEREXPRESSION; MORPHOGENESIS;
D O I
10.1038/sj.bjc.6604937
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
There is a pressing need to identify new drug targets and novel approaches for treatment of non-small-cell lung carcinoma (NSCLC). Members of the epidermal growth factor receptor (EGFR) and Met receptor families have been identified as important molecular targets for NSCLC. Two EGFR tyrosine kinase inhibitors (TKIs; erlotinib and gefitinib) are in current clinical use, but a majority of patients do not respond to these targeted therapies. We used receptor TK (RTK) capture arrays to identify receptors active in NSCLC cell lines. As Met and ErbBs were active, we explored the potential therapeutic advantage of combined targeting of Met with ErbB receptor family inhibitors for treatment of NSCLC. We found that Met physically interacts with both EGFR and Her2 in a NSCLC cell line with overexpression/overactivation of Met. Combined use of a dual EGFR/Her2 inhibitor with a Met inhibitor yields maximal growth inhibition compared with the use of EGFR and/or Met inhibitors. This suggests that simultaneous inhibition of multiple RTKs may be needed to effectively abrogate tumour cell growth. Phosphoproteomic analysis by RTK capture arrays may be a valuable tool for identifying the subset of tumours with functional receptor activation, regardless of mechanism.
引用
收藏
页码:941 / 949
页数:9
相关论文
共 36 条
[1]   HER3 and mutant EGFR meet MET [J].
Arteaga, Carlos L. .
NATURE MEDICINE, 2007, 13 (06) :675-677
[2]   Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor - Mutant lung adenocarcinomas with acquired resistance to kinase inhibitors [J].
Balak, Marissa N. ;
Gong, Yixuan ;
Riely, Gregory J. ;
Somwar, Romel ;
Li, Allan R. ;
Zakowski, Maureen F. ;
Chiang, Anne ;
Yang, Guangli ;
Ouerfelli, Ouathek ;
Kris, Mark G. ;
Ladanyi, Marc ;
Miller, Vincent A. ;
Pao, William .
CLINICAL CANCER RESEARCH, 2006, 12 (21) :6494-6501
[3]   MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib [J].
Bean, James ;
Brennan, Cameron ;
Shih, Jin-Yuan ;
Riely, Gregory ;
Viale, Agnes ;
Wang, Lu ;
Chitale, Dhananjay ;
Motoi, Noriko ;
Szoke, Janos ;
Broderick, Stephen ;
Balak, Marissa ;
Chang, Wen-Cheng ;
Yu, Chong-Jen ;
Gazdar, Adi ;
Pass, Harvey ;
Rusch, Valerie ;
Gerald, William ;
Huang, Shiu-Feng ;
Yang, Pan-Chyr ;
Miller, Vincent ;
Ladany, Marc ;
Yang, Chih-Hsin ;
Pao, William .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (52) :20932-20937
[4]  
Christensen JG, 2003, CANCER RES, V63, P7345
[5]   Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis [J].
Day, RM ;
Cioce, V ;
Breckenridge, D ;
Castagnino, P ;
Bottaro, DP .
ONCOGENE, 1999, 18 (22) :3399-3406
[6]   Hepatocyte growth factor in invasive growth of carcinomas [J].
Desiderio, M. A. .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2007, 64 (11) :1341-1354
[7]   ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines [J].
Engelman, JA ;
Jänne, PA ;
Mermel, C ;
Pearlberg, J ;
Mukohara, T ;
Fleet, C ;
Cichowski, K ;
Johnson, BE ;
Cantley, LC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (10) :3788-3793
[8]   MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling [J].
Engelman, Jeffrey A. ;
Zejnullahu, Kreshnik ;
Mitsudomi, Tetsuya ;
Song, Youngchul ;
Hyland, Courtney ;
Park, Joon Oh ;
Lindeman, Neal ;
Gale, Christopher-Michael ;
Zhao, Xiaojun ;
Christensen, James ;
Kosaka, Takayuki ;
Holmes, Alison J. ;
Rogers, Andrew M. ;
Cappuzzo, Federico ;
Mok, Tony ;
Lee, Charles ;
Johnson, Bruce E. ;
Cantley, Lewis C. ;
Janne, Pasi A. .
SCIENCE, 2007, 316 (5827) :1039-1043
[9]   Proliferation and invasion: Plasticity in tumor cells [J].
Gao, CF ;
Xie, Q ;
Su, YL ;
Koeman, J ;
Khoo, SK ;
Gustafson, M ;
Knudsen, BS ;
Hay, R ;
Shinomiya, N ;
Woude, GFV .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (30) :10528-10533
[10]   HGF/SF-Met signaling in tumor progression [J].
Gao, CF ;
Vande Woude, GF .
CELL RESEARCH, 2005, 15 (01) :49-51