A combinatorial strategy for overcoming primary and acquired resistance of MEK inhibition in colorectal cancer
A combinatorial strategy for overcoming primary and acquired resistance of MEK inhibition in colorectal cancer
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DOI：
10.1016/j.yexcr.2020.112060
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发表时间：
2020-08-01
影响因子：
3.7
通讯作者：
Yang, Tao
中科院分区：
文献类型：
--
作者：
Chen, Junjun;Dai, Jie;Yang, Tao
与传统化疗药物相比，靶向治疗药物具有疗效高、毒副作用小等优点。然而，在大肠癌的临床治疗实践中，这些药物的原发性和获得性耐药限制了其靶向治疗的有效性，从而阻碍了精准医疗和个体化治疗的发展。目前，用于结直肠癌靶向治疗的药物数量有限，主要是针对EGFR的单克隆抗体或VEGFR抑制剂。曲美替尼是一种MEK抑制剂，已成功应用于黑色素瘤患者，但由于其耐药性，尚未用于结直肠癌的临床治疗。为了确定大肠癌细胞对曲美替尼的耐药机制并找到有用的化学组合来克服耐药性，我们首先筛选原代和获得的细胞系，然后使用Chou-Talalay方法测试多个协同药物组合。我们获得了原发性耐药细胞系SW 480、CW-2和获得性耐药细胞系RKO-R以及曲美替尼和GSK 2126458的协同组合。该组合抑制结直肠癌细胞的殖民地形成和裸鼠中异种移植肿瘤的生长。机制分析表明，曲美替尼可激活PI 3 K-AKT旁路信号通路，同时抑制MAPK通路，这可能是大肠癌细胞原发性和获得性曲美替尼耐受的分子机制之一。重要的是，这种旁路激活可以被GSK 2126458阻断。这些结果表明，曲美替尼和GSK 2126458的组合是治疗对曲美替尼耐药的结直肠癌的有效方法。
Compared with traditional chemotherapeutic drugs, targeted therapeutic medicine has the advantages of high efficacy and less toxic side effects. However, in clinical practice for treatment of colorectal cancer, the primary and acquired resistance of these medicines limits their effectiveness in targeted therapy, therefore impedes the development of precision medicine and personalized therapy. Currently, there are limited number of drugs for targeted therapy of colorectal cancer, mainly monoclonal antibodies against EGFR or VEGFR inhibitors. Trametinib, a MEK inhibitor, has been applied in melanoma patient successfully, but not been used in clinical treatment of colorectal cancer because of its drug resistance. To identify the resistance mechanism of colorectal cancer cells to trametinib and find useful chemical combination to overcome the resistance, we screened primary and acquired cell line first and then tested multiple synergistic drug combinations by using the Chou-Talalay method. We obtained the primary resistant cell lines SW480, CW-2 and the acquired drug-resistant cell line RKO-R as well as a synergistic combination of trametinib and GSK2126458. This combination inhibits the colony formation of colorectal cancer cells and the growth of xenograft tumors in nude mice. Mechanistic analysis showed that trametinib can activate the alternative PI3K-AKT signaling pathway while inhibiting the MAPK pathway, which may be one of the molecular mechanisms of primary and acquired trametinib tolerance in colorectal cancer cells. Importantly, this bypass activation can be blocked by GSK2126458. These results suggest that a combination of trametinib and GSK2126458 is an effective approach for treating colorectal cancer resistance to trametinib.