Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy
Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy
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DOI：
10.18632/oncotarget.17438
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发表时间：
2017-07-11
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影响因子：
--
通讯作者：
Schuler, Martin
中科院分区：
文献类型：
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作者：
Kasper, Stefan;Reis, Henning;Schuler, Martin
靶向表皮生长因子受体（EGFR）的单克隆抗体西妥昔单抗和帕尼单抗是转移性结直肠癌（mCRC）治疗的主要药物。然而，相当数量的患者患有原发性或获得性耐药。RAS突变是抗EGFR抗体在mCRC患者中临床疗效的阴性预测因子。致癌性RAS激活MAPK和PI 3 K/AKT通路，这被认为是耐药的主要效应子。然而，这些途径在RAS突变型CRC中的相对影响尚不明确。更好地了解RAS介导的耐药机制可能会指导合理干预策略的制定。为此，我们开发了用于体外和体内抗EGFR治疗抗性的功能解剖的癌症模型。为了选择性激活MAPK或AKT信号传导，我们在癌细胞中表达了条件激活的RAF-1和AKT。我们发现，无论是在体外还是在体内，这两种途径都能独立地保护敏感的癌症模型免受抗EGFR抗体治疗。RAF-1和AKT介导的抗性与抗凋亡BCL-2蛋白表达增加相关。MAPK和PI 3 K/AKT通路激活的生物标志物与接受西妥昔单抗治疗的mCRC患者队列的不良结局相关。PI 3 K和MEK的双重药理学抑制成功地使原发性耐药CRC模型对抗EGFR治疗敏感。总之，可能需要MAPK和PI 3 K/AKT信号传导的组合靶向，而不是单一途径，以增强抗EGFR抗体治疗在RAS突变CRC患者以及具有临床耐药性的RAS野生型肿瘤中的疗效。
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC. Oncogenic RAS activates the MAPK and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways in RAS-mutant CRC is less defined. A better mechanistic understanding of RAS-mediated resistance may guide development of rational intervention strategies. To this end we developed cancer models for functional dissection of resistance to anti-EGFR therapy in vitro and in vivo. To selectively activate MAPK-or AKT-signaling we expressed conditionally activatable RAF-1 and AKT in cancer cells. We found that either pathway independently protected sensitive cancer models against anti-EGFR antibody treatment in vitro and in vivo. RAF-1-and AKT-mediated resistance was associated with increased expression of anti-apoptotic BCL-2 proteins. Biomarkers of MAPK and PI3K/AKT pathway activation correlated with inferior outcome in a cohort of mCRC patients receiving cetuximab-based therapy. Dual pharmacologic inhibition of PI3K and MEK successfully sensitized primary resistant CRC models to anti-EGFR therapy. In conclusion, combined targeting of MAPK and PI3K/AKT signaling, but not single pathways, may be required to enhance the efficacy of anti-EGFR antibody therapy in patients with RAS-mutated CRC as well as in RAS wild type tumors with clinical resistance.