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 cancer cells

Teresa Troiani, Erika Martinelli, Stefania Napolitano, Donata Vitagliano, Loreta Pia Ciuffreda, Sara Costantino, Floriana Morgillo, Anna Capasso, Vincenzo Sforza, Anna Nappi, Raffaele De Palma, Elena D'Aiuto, Liberato Berrino, Roberto Bianco, Fortunato Ciardiello

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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-CRcells, 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-CRcells. Furthermore, activated, phosphorylatedMETwas 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 METby 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-a, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-a 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-a 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.

Original languageEnglish
Pages (from-to)6751-6765
Number of pages15
JournalClinical Cancer Research
Volume19
Issue number24
DOIs
Publication statusPublished - Dec 15 2013

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Troiani, T., Martinelli, E., Napolitano, S., Vitagliano, D., Ciuffreda, L. P., Costantino, S., Morgillo, F., Capasso, A., Sforza, V., Nappi, A., De Palma, R., D'Aiuto, E., Berrino, L., Bianco, R., & Ciardiello, F. (2013). 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 cancer cells. Clinical Cancer Research, 19(24), 6751-6765. https://doi.org/10.1158/1078-0432.CCR-13-0423