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Int. J. Mol. Sci. 2014, 15(4), 5838-5851; doi:10.3390/ijms15045838

Cetuximab-Induced MET Activation Acts as a Novel Resistance Mechanism in Colon Cancer Cells

*  and *
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China
* Authors to whom correspondence should be addressed.
Received: 4 February 2014 / Revised: 18 March 2014 / Accepted: 26 March 2014 / Published: 4 April 2014
(This article belongs to the Section Biochemistry, Molecular Biology and Biophysics)
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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.
Keywords: cetuximab; MET; EGFR; SRC; colon cancer cetuximab; MET; EGFR; SRC; colon cancer
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Song, N.; Liu, S.; Zhang, J.; Liu, J.; Xu, L.; Liu, Y.; Qu, X. Cetuximab-Induced MET Activation Acts as a Novel Resistance Mechanism in Colon Cancer Cells. Int. J. Mol. Sci. 2014, 15, 5838-5851.

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