Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade
Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade
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DOI：
10.1038/onc.2012.302
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发表时间：
2013-06-06
期刊：
影响因子：
8
通讯作者：
Schuler, M.
中科院分区：
文献类型：
--
作者：
Kasper, S.;Breitenbuecher, F.;Schuler, M.
针对表皮生长因子受体 (EGFR) 的单克隆抗体是有效的癌症治疗方法，但携带 RAS 突变的肿瘤具有耐药性。为了从功能上剖析 RAS 介导的耐药性，我们在癌症模型中研究了临床批准的抗 EGFR 抗体西妥昔单抗和帕尼单抗。两种抗体在体外具有相同的细胞毒性。然而，西妥昔单抗也会引发抗体依赖性细胞毒性（ADCC），在体内比帕尼单抗更有效。致癌 RAS 在体内中和了两种抗体的活性。从机制上讲，RAS 上调癌细胞系和原发性结直肠癌中的 BCL-XL。通过短发夹 RNA 抑制 BCL-XL 或用 BH3 模拟物治疗克服了 RAS 介导的抗体耐药性。总之，RAS 突变肿瘤在体内逃脱了抗 EGFR 抗体介导的受体阻断以及 ADCC。 RAS 效应子的药理学靶向可以恢复对抗体治疗的敏感性。
Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are effective cancer therapeutics, but tumors harboring RAS mutations are resistant. To functionally dissect RAS-mediated resistance, we have studied clinically approved anti-EGFR antibodies, cetuximab and panitumumab, in cancer models. Both antibodies were equally cytotoxic in vitro. However, cetuximab, which also triggers antibody-dependent cellular cytotoxicity (ADCC), was more effective than panitumumab in vivo. Oncogenic RAS neutralized the activity of both antibodies in vivo. Mechanistically, RAS upregulated BCL-XL in cancer cell lines and in primary colorectal cancers. Suppression of BCL-XL by short hairpin RNA or treatment with a BH3 mimetic overcame RAS-mediated antibody resistance. In conclusion, RAS-mutant tumors escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacological targeting of RAS effectors can restore sensitivity to antibody therapy.