Research Papers:

The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells

Hisato Kawakami _, Isamu Okamoto, Kimio Yonesaka, Kunio Okamoto, Kiyoko Shibata, Yume Shinkai, Haruka Sakamoto, Michiko Kitano, Takao Tamura, Kazuto Nishio and Kazuhiko Nakagawa

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Oncotarget. 2014; 5:11847-11856. https://doi.org/10.18632/oncotarget.2663

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Hisato Kawakami1, Isamu Okamoto1,2, Kimio Yonesaka1, Kunio Okamoto1, Kiyoko Shibata1, Yume Shinkai1, Haruka Sakamoto1, Michiko Kitano1, Takao Tamura1, Kazuto Nishio3, Kazuhiko Nakagawa1

1Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-sayama, Osaka 589-8511, Japan

2Center for Clinical and Translational Research, Kyushu University Hospital, Higashiku, Fukuoka 812–8582, Japan

3Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Osaka 589–8511, Japan

Correspondence to:

Isamu Okamoto, e-mail: [email protected]

Keywords: colorectal cancer, heregulin, resistance, cetuximab, patritumab

Received: September 21, 2014     Accepted: October 26, 2014     Published: December 19, 2014


We previously showed that tumor-derived heregulin, a ligand for HER3, is associated with both de novo and acquired resistance to cetuximab. We have now examined whether patritumab, a novel neutralizing monoclonal antibody to HER3, is able to overcome such resistance. Human colorectal cancer (DiFi) cells that are highly sensitive to cetuximab were engineered to stably express heregulin by retroviral infection, and the effects of cetuximab and patritumab on the resulting DiFi-HRG cells were examined. DiFi-HRG cells released substantial amounts of heregulin and showed resistance to cetuximab. Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies cetuximab resistance in these cells. In contrast, patritumab in combination with cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination therapy also inhibited the growth of DiFi-HRG tumor xenografts in nude mice to a greater extent than did treatment with either drug alone. Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin-induced HER3 activation.

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