Increased TGF-α as a mechanism of acquired resistance to the anti-EGFR inhibitor cetuximab through EGFR–MET interaction and activation of MET signaling in colon …
T Troiani, E Martinelli, S Napolitano, D Vitagliano… - Clinical cancer …, 2013 - AACR
T Troiani, E Martinelli, S Napolitano, D Vitagliano, LP Ciuffreda, S Costantino, F Morgillo…
Clinical cancer research, 2013•AACRPurpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an
effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its
clinical use is limited by onset of resistance. Experimental Design: We characterized two
colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.
Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO
colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells …
effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its
clinical use is limited by onset of resistance. Experimental Design: We characterized two
colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.
Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO
colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells …
Abstract
Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance.
Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.
Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET–dependent pathways, which were upregulated in GEO-CR cells. Furthermore, activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenous activation of MET by HGF stimulation in cetuximab-sensitive GEO and SW48 cells induced resistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-α, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-α overexpression induced the EGFR–MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.
Conclusions: These results suggest that overexpression of TGF-α through induction of EGFR–MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer. Clin Cancer Res; 19(24); 6751–65. ©2013 AACR.
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