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

摘要: // Hisato Kawakami 1 , Isamu Okamoto 1, 2 Kimio Yonesaka Kunio Kiyoko Shibata Yume Shinkai Haruka Sakamoto Michiko Kitano Takao Tamura Kazuto Nishio 3 Kazuhiko Nakagawa Department of Medical Oncology, Kinki University Faculty Medicine, Osaka-sayama, Osaka 589-8511, Japan Center for Clinical and Translational Research, Kyushu Hospital, Higashiku, Fukuoka 812–8582, Genome Biology, Osaka-Sayama, 589–8511, Correspondence to: Okamoto, e-mail: okamotoi@kokyu.med.kyushu-u.ac.jp Keywords: colorectal cancer, heregulin, resistance, cetuximab, patritumab Received: September 21, 2014      Accepted: October 26, Published: December 19, 2014 ABSTRACT We previously showed that tumor-derived a ligand HER3, is associated with both de novo acquired resistance to cetuximab. have now examined whether patritumab, novel neutralizing monoclonal antibody able overcome such resistance. Human cancer (DiFi) cells are highly sensitive cetuximab were engineered stably express heregulin by retroviral infection, the effects on resulting DiFi-HRG examined. released substantial amounts Cetuximab alone inhibited EGFR ERK phosphorylation in cells, but it had no effect HER2, or AKT, suggesting sustained AKT activation HER2 HER3 underlies these cells. In contrast, combination markedly EGFR, ERK, AKT. The therapy also growth tumor xenografts nude mice greater extent than did treatment either drug alone. Activation HER2-HER3 signaling operation autocrine loop confers restore sensitivity through inhibition heregulin-induced activation.