Failure of clinical trials due to development of resistance to MET-targeting therapeutic agents is an emerging problem. Mechanisms of acquired resistance to MET tyrosine kinase inhibitors are well described, whereas characterization of mechanisms of resistance toward MET-targeting antibodies is limited. This study investigated mechanisms underlying in vivo resistance to two antibody therapeutics currently in clinical development: an analogue of the MET-targeting antibody emibetuzumab and Sym015, a mixture of two antibodies targeting nonoverlapping epitopes of MET. Upon long-term in vivo treatment of a MET-amplified gastric cancer xenograft model (SNU-5), emibetuzumab-resistant, but not Sym015-resistant, tumors emerged. Resistant tumors were isolated and used to establish resistant cell lines. Characterization of both tumors and cell lines using extensive protein and signaling pathway activation mapping along with next-generation sequencing revealed two distinct resistance profiles, one involving PTEN loss and the other involving activation of the PI3K pathway, likely via MYC and ERBB3 copy number gains. PTEN loss left one model unaffected by PI3K/AKT targeting but sensitive to mTOR targeting, while the PI3K pathway–activated model was partly sensitive to targeting of multiple PI3K pathway proteins. Importantly, both resistant models were sensitive to treatment with Sym015 in vivo due to antibody-dependent cellular cytotoxicity–mediated tumor growth inhibition, MET degradation, and signaling inhibition. Taken together, our data provide key insights into potential mechanisms of resistance to a single MET-targeting antibody, demonstrate superiority of Sym015 in preventing acquired resistance, and confirm Sym015 antitumor activity in tumors resistant to a single MET antibody. Mol Cancer Ther; 17(6); 1259–70. ©2018 AACR.

中文翻译：

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MET 抗体混合物 Sym015 可以克服体内对 MET 抗体的获得性抗性

由于对 MET 靶向治疗剂产生耐药性而导致临床试验失败是一个新出现的问题。对 MET 酪氨酸激酶抑制剂的获得性抗性的机制已有很好的描述，而对 MET 靶向抗体的抗性机制的表征是有限的。本研究调查了目前临床开发中的两种抗体疗法的体内抗性机制：MET 靶向抗体 emibetuzumab 的类似物和 Sym015，Sym015 是两种靶向非重叠 MET 表位的抗体的混合物。在对 MET 扩增的胃癌异种移植模型 (SNU-5) 进行长期体内治疗后，出现了 emibetuzumab 抗性但不抗 Sym015 的肿瘤。分离抗性肿瘤并用于建立抗性细胞系。使用广泛的蛋白质和信号通路激活作图以及下一代测序对肿瘤和细胞系进行表征，揭示了两种不同的耐药谱，一种涉及 PTEN 丢失，另一种涉及 PI3K 通路的激活，可能通过 MYC 和 ERBB3 拷贝数增加。PTEN 缺失使一种模型不受 PI3K/AKT 靶向但对 mTOR 靶向敏感，而 PI3K 通路激活模型对多种 PI3K 通路蛋白的靶向部分敏感。重要的是，由于抗体依赖性细胞毒性介导的肿瘤生长抑制、MET 降解和信号抑制，两种耐药模型都对 Sym015 体内 治疗敏感。总之，我们的数据提供了对单一 MET 靶向抗体的潜在耐药机制的关键见解，证明了 Sym015 在预防获得性耐药方面的优势，并证实了 Sym015 在对单一 MET 抗体耐药的肿瘤中的抗肿瘤活性。摩尔癌症治疗; 17(6); 1259-70。©2018 AACR。