Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.

Abstract

Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers.

• Authors: Kimio Yonesaka, Kreshnik Zejnullahu, Isamu Okamoto, Taroh Satoh, Federico Cappuzzo, John Souglakos, Dalia Ercan, Andrew Rogers, Massimo Roncalli, Masayuki Takeda, Yasuhito Fujisaka, Juliet Philips, Toshio Shimizu, Osamu Maenishi, Yonggon Cho, Jason Sun, Annarita Destro, Koichi Taira, Koji Takeda, Takafumi Okabe, Jeffrey Swanson, Hiroyuki Itoh, Minoru Takada, Eugene Lifshits, Kiyotaka Okuno, Jeffrey A Engelman, Ramesh A Shivdasani, Kazuto Nishio, Masahiro Fukuoka, Marileila Varella-Garcia, Kazuhiko Nakagawa, Pasi A Jänne
• Journal: Science translational medicine (Sci Transl Med) Vol. 3 Issue 99 Pg. 99ra86 (Sep 07 2011) ISSN: 1946-6242 [Electronic] United States
• PMID: 21900593 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Neuregulin-1
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Cetuximab

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (therapeutic use)
• Cell Line, Tumor
• Cetuximab
• Drug Resistance, Neoplasm
• ErbB Receptors (genetics, metabolism)
• Humans
• Mice
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Neoplasm Transplantation
• Neoplasms (drug therapy, metabolism)
• Neuregulin-1 (genetics, metabolism)
• Receptor, ErbB-2 (genetics, metabolism)
• Signal Transduction (physiology)
• Transplantation, Heterologous