Study points to strategy for overcoming resistance to targeted cancer drug

BOSTON -- 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 Janne, 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 Janne, 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."

Janne 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.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women's Hospital as Dana-Farber/Brigham and Women's Cancer Center and it provides pediatric care with Children's Hospital Boston as Dana-Farber/Children's Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.

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