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.

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 24 Pg. 6751-65 (Dec 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 24122793 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR.

Chemical References

• Antibodies, Monoclonal, Humanized
• Transforming Growth Factor alpha
• Hepatocyte Growth Factor
• EGFR protein, human
• ErbB Receptors
• MET protein, human
• Proto-Oncogene Proteins c-met
• Cetuximab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cetuximab
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Hepatocyte Growth Factor (biosynthesis)
• Humans
• Mice
• Proto-Oncogene Proteins c-met (genetics, metabolism)
• Signal Transduction (drug effects)
• Transforming Growth Factor alpha (biosynthesis)