Cetuximab-induced MET activation acts as a novel resistance mechanism in colon cancer cells.
Aberrant MET expression and hepatocyte growth factor (HGF) signaling are implicated in promoting resistance to targeted agents; however, the induced MET activation by epidermal growth factor receptor (EGFR) inhibitors mediating resistance to targeted therapy remains elusive. In this study, we identified that cetuximab-induced MET activation contributed to cetuximab resistance in Caco-2 colon cancer cells. MET inhibition or knockdown sensitized Caco-2 cells to cetuximab-mediated growth inhibition. Additionally, SRC activation promoted cetuximab resistance by interacting with MET. Pretreatment with SRC inhibitors abolished cetuximab-mediated MET activation and rendered Caco-2 cells sensitive to cetuximab. Notably, cetuximab induced MET/SRC/EGFR complex formation. MET inhibitor or SRC inhibitor suppressed phosphorylation of MET and SRC in the complex, and MET inhibitor singly led to disruption of complex formation. These results implicate alternative targeting of MET or SRC as rational strategies for reversing cetuximab resistance in colon cancer.
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. songna_cmu@hotmail.com.
Na
N
Song
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. liu_shizhou@hotmail.com.
Shizhou
S
Liu
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. jd_zhang@hotmail.com.
Jingdong
J
Zhang
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. liujing_cmu@hotmail.com.
Jing
J
Liu
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. cmuxuling@hotmail.com.
Ling
L
Xu
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. ypliu@mail.cmu.edu.cn.
Yunpeng
Y
Liu
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. cmuquxiujuan@gmail.com.
Xiujuan
X
Qu
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D034741:RNA, Small Interfering; D018631:ras Proteins / Q000235:genetics; D019061:src-Family Kinases / Q000378:metabolism
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C066855:HGF protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D019061:src-Family Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab