Overcoming Cetuximab Resistance In Cancer Treatment Possible With ERBB2 inhibitors.

Kimio Yonesaka, MD, PhD, formerly of Dana-Farber and now at Kinki University School of Medicine, in Osaka, Japan, together with other scientists including Pasi Jänne, MD, PhD, of Dana-Farber , have discovered a pair of backup circuits in cancer cells that enable the cells to bypass the effect of a widely used cancer drug cetuximab, an antibody that interferes with cancer cell growth by blocking a structure known as the epidermal growth factor receptor (EGFR).
Their research found out that interfering the said backup circuits ERBB2 with targeted therapies may heighten or restore the cetuximab’s potency. The paper covering the study is published in the Sept. 7 issue of Science Translational Medicine.
"ERBB2 activates a critical signaling pathway that is not normally blocked by cetuximab, and in this way subverts cetuximab’s function, Because ERBB2 isn’t affected by cetuximab, this is an easy way for cancers to become resistant to the drug."" says Jänne, the study's co-senior author with Kazuhiko Nakagawa, MD, PhD, of Kinki University.
"We hope the findings of our study will inspire the development of clinical trials aimed at overcoming cetuximab resistance, We've identified biomarkers that can be used to select cetuximab-resistant patients who may benefit from a combination of cetuximab and ERBB2 inhibitors."" Yonesaka remarks.

Abstract from Science Translational Medicine.

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. 

Dana-Farber Press Release;

September 07, 2011 Scientists at Dana-Farber Cancer Institute and colleagues overseas have discovered a pair of backup circuits in cancer cells that enable the cells to dodge the effect of a widely used cancer drug. Jamming those circuits with targeted therapies may heighten or restore the drug’s potency, according to a study published in the Sept. 7 issue of Science Translational Medicine.

The research focused on the drug cetuximab, an antibody that interferes with cancer cell growth by blocking a structure known as the epidermal growth factor receptor (EGFR). Cetuximab is effective in many patients with colorectal cancer or squamous cell cancer of the head and neck, but the benefits rarely last longer than a year, and some patients receive no benefit from the drug.

Until now, scientists haven't known why cancers that initially respond to cetuximab become resistant to it, or how to overcome such resistance.

In the new study, researchers led by Pasi Jänne, MD, PhD, of Dana-Farber and Kimio Yonesaka, MD, PhD, formerly of Dana-Farber and now at Kinki University School of Medicine, in Osaka, Japan, found that in some cetuximab-resistant cancer cells, a protein known as ERBB2 was actively sending "grow" signals, circumventing the "stop growing" signals triggered by cetuximab. The researchers discovered that ERBB2's activity sprang from an oversupply of the protein’s parent gene, Her2/neu, or by a related protein, ERBB3, when prompted by high levels of the protein heregulin. In both cases, the new growth messages are unaffected by cetuximab.

"ERBB2 activates a critical signaling pathway that is not normally blocked by cetuximab, and in this way subverts cetuximab’s function," says Jänne, the study's co-senior author with Kazuhiko Nakagawa, MD, PhD, of Kinki University. "Because ERBB2 isn’t affected by cetuximab, this is an easy way for cancers to become resistant to the drug."

The findings suggest that combining cetuximab with ERBB2-inhibiting drugs could be an effective therapy for cancers that are cetuximab-resistant from the start or for those that become resistant over time, the study authors say. Several such inhibitors have already been approved, while others are undergoing clinical study.

"We hope the findings of our study will inspire the development of clinical trials aimed at overcoming cetuximab resistance," Yonesaka remarks. "We've identified biomarkers that can be used to select cetuximab-resistant patients who may benefit from a combination of cetuximab and ERBB2 inhibitors."

Jänne estimates that up to 40 percent of colorectal cancers are cetuximab-resistant when first diagnosed. He notes that although the ERBB2 pathway may be responsible for many cases of cetuximab resistance, there are undoubtedly other pathways, yet to be discovered, that play a similar role. Further research is needed to confirm ERBB2's role in cetuximab resistance and to develop strategies for testing ERBB2 inhibitors and cetuximab in clinical trials.

Funding for the study was provided by grants from the National Institutes of Health, the American Cancer Society, the William Randolph Hearst Foundation, and the Hazel and Samuel Bellin research fund.

Co-authors of the paper include Kreshnik Zejnullahu, Dalia Ercan, Andrew Rogers, Juliet Philips, MS, Jason Sun, Takafumi Okabe, MD, PhD, Jeffrey Swanson, MD, and Ramesh Shivdasani, MD, PhD, Dana-Farber; Isamu Okamoto, MD, PhD, Taroh Satoh, MD, Masayuki Takeda, MD, PhD, Yasuhito Fujisaka, MD, Toshio Shimizu, MD, PhD, Osamu Maenishi, Hiroyuki Itoh, MD, Kiyotaka Okuno, MD, Minoru Takada, MD, Masahiro Fukuoka, MD, and Kazuto Nishio, MD, PhD, Kinki University, Osaka, Japan; Federico Cappuzzo, MD, Massimo Roncalli, MD, and Annarita Destro, PhD, Instituto Clinico Humanitas, Rozzano, Italy; John Souglakos, MD, PhD, University of Crete, Heraklion, Greece; Yonggon Cho, and Marileila Varella-Garcia, University of Colorado Cancer Center, Denver; Koichi Taira, MD, and Koji Takeda, MD, Osaka City General Hospital, Japan; and Eugene Lifshits and Jeffrey Engelman, MD, PhD, Massachusetts General Hospital.

cetuximab  (From NCI Drug Dictionary) 
A recombinant, chimeric monoclonal antibody directed against the epidermal growth factor (EGFR) with antineoplastic activity. Cetuximab binds to the extracellular domain of the EGFR, thereby preventing the activation and subsequent dimerization of the receptor; the decrease in receptor activation and dimerization may result in an inhibition in signal transduction and anti-proliferative effects. This agent may inhibit EGFR-dependent primary tumor growth and metastasis. EGFR is overexpressed on the cell surfaces of various solid tumors. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Synonyms:		Anti-EGFR Monoclonal Antibody Anti-Epidermal Growth Factor Receptor Monoclonal Antibody C225 monoclonal antibody Chimeric Anti-EGFR Monoclonal Antibody Chimeric Monoclonal Antibody C225 Immunoglobulin G1, anti-(human epidermal growth factor receptor) (human-mouse monoclonal C225 gamma1-chain), disulfide with human-mouse monoclonal C225 kappa-chain, dimer monoclonal antibody C225
US brand name:		Erbitux
Abbreviations:		Chimeric MoAb C225 MOAB C225
Code names:		C225 IMC-C225