title: 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: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Kimio
authors: K
authors: Yonesaka
authors: Kreshnik
authors: K
authors: Zejnullahu
authors: Isamu
authors: I
authors: Okamoto
authors: Taroh
authors: T
authors: Satoh
authors: Federico
authors: F
authors: Cappuzzo
authors: John
authors: J
authors: Souglakos
authors: Dalia
authors: D
authors: Ercan
authors: Andrew
authors: A
authors: Rogers
authors: Massimo
authors: M
authors: Roncalli
authors: Masayuki
authors: M
authors: Takeda
authors: Yasuhito
authors: Y
authors: Fujisaka
authors: Juliet
authors: J
authors: Philips
authors: Toshio
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authors: Shimizu
authors: Osamu
authors: O
authors: Maenishi
authors: Yonggon
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authors: Cho
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authors: Sun
authors: Annarita
authors: A
authors: Destro
authors: Koichi
authors: K
authors: Taira
authors: Koji
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authors: Takeda
authors: Takafumi
authors: T
authors: Okabe
authors: Jeffrey
authors: J
authors: Swanson
authors: Hiroyuki
authors: H
authors: Itoh
authors: Minoru
authors: M
authors: Takada
authors: Eugene
authors: E
authors: Lifshits
authors: Kiyotaka
authors: K
authors: Okuno
authors: Jeffrey A
authors: JA
authors: Engelman
authors: Ramesh A
authors: RA
authors: Shivdasani
authors: Kazuto
authors: K
authors: Nishio
authors: Masahiro
authors: M
authors: Fukuoka
authors: Marileila
authors: M
authors: Varella-Garcia
authors: Kazuhiko
authors: K
authors: Nakagawa
authors: Pasi A
authors: PA
authors: Jänne
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human