Cetuximab-induced MET activation acts as a novel resistance mechanism in colon cancer cells

Na Song; Shizhou Liu; Jingdong Zhang; Jing Liu; Ling Xu; Yunpeng Liu; Xiujuan Qu

doi:10.3390/ijms15045838

Cetuximab-induced MET activation acts as a novel resistance mechanism in colon cancer cells

Int J Mol Sci. 2014 Apr 4;15(4):5838-51. doi: 10.3390/ijms15045838.

Authors

Na Song¹, Shizhou Liu², Jingdong Zhang³, Jing Liu⁴, Ling Xu⁵, Yunpeng Liu⁶, Xiujuan Qu⁷

Affiliations

¹ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. songna_cmu@hotmail.com.
² Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. liu_shizhou@hotmail.com.
³ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. jd_zhang@hotmail.com.
⁴ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. liujing_cmu@hotmail.com.
⁵ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. cmuxuling@hotmail.com.
⁶ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. ypliu@mail.cmu.edu.cn.
⁷ Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China. cmuquxiujuan@gmail.com.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal, Humanized / pharmacology*
Antineoplastic Agents / pharmacology*
Caco-2 Cells
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cetuximab
Colonic Neoplasms / drug therapy*
Drug Resistance, Neoplasm / drug effects
Enzyme Activation
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
HCT116 Cells
HT29 Cells
Hepatocyte Growth Factor / metabolism
Humans
Protein Binding
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins c-met / biosynthesis
Proto-Oncogene Proteins c-met / genetics
Proto-Oncogene Proteins c-met / metabolism*
Proto-Oncogene Proteins p21(ras)
RNA Interference
RNA, Small Interfering
ras Proteins / genetics
src-Family Kinases / metabolism

Substances

Antibodies, Monoclonal, Humanized
Antineoplastic Agents
HGF protein, human
KRAS protein, human
Proto-Oncogene Proteins
RNA, Small Interfering
Hepatocyte Growth Factor
EGFR protein, human
ErbB Receptors
MET protein, human
Proto-Oncogene Proteins c-met
src-Family Kinases
Proto-Oncogene Proteins p21(ras)
ras Proteins
Cetuximab