MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in KRAS-mutated Human Colorectal Cancer Cell Lines.
MEK162 Enhances Antitumor Activity of 5-Fluorouracil and Trifluridine in KRAS-mutated Human Colorectal Cancer Cell Lines.
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DOI：
10.21873/anticanres.11634
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发表时间：
2017-06
影响因子：
2
通讯作者：
Fakih M
中科院分区：
文献类型：
--
作者：
Gong J;Chen Y;Yang L;Pillai R;Shirasawa S;Fakih M
临床前证据表明，丝裂原激活蛋白激酶激酶 (MEK)/细胞外信号调节激酶 (ERK) 通路抑制可增加结直肠癌 (CRC) 细胞系和异种移植物对 5-氟尿嘧啶 (5-FU) 的敏感性。在这里，我们的目的是研究 CRC 细胞对这种组合的敏感性如何与 Kirsten 大鼠肉瘤 (KRAS) 和原癌基因 B 快速加速纤维肉瘤 (BRAF) 突变相关，这些突变在 CRC 中很常见，通常会导致化疗耐药。将野生型和突变型 KRAS/BRAF 人 CRC 细胞系用递增剂量的 5-FU 或三氟尿苷与 MEK162（MEK1/2 抑制剂）处理 72 小时。通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑测定评估细胞活力，并使用CalcuSyn计算组合指数表达的协同作用。在用 MEK162 加 5-FU (4/6) 或曲氟尿苷 (7/9) 处理的大多数人 CRC 细胞系中观察到协同抗肿瘤活性的证据。与野生型 KRAS/BRAF CRC 细胞系相比，KRAS 或 BRAF 突变细胞系的协同作用更强。 MEK 抑制剂和三氟尿苷的组合值得在临床开发中推进，特别是对于难治性 KRAS 或 BRAF 突变的转移性 CRC。
Preclinical evidence demonstrates that mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are common in CRC and often lead to resistance to chemotherapy. Wild-type and mutant KRAS/BRAF human CRC cell lines were treated with escalating doses of 5-FU or trifluridine with MEK162 (MEK1/2 inhibitor) for 72 h. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and synergism expressed by the combination index was calculated using CalcuSyn. Evidence of synergistic antitumor activity was observed for the majority of human CRC cell lines treated with MEK162 plus 5-FU (4/6) or trifluridine (7/9). Synergism was greater in KRAS- or BRAF-mutant cell lines compared to wild-type KRAS/BRAF CRC cell lines. The combination of MEK inhibition and trifluridine is worthwhile advancing in clinical development, particularly for treatment-refractory KRAS- or BRAF-mutated metastatic CRC.
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影响因子：
11.2
作者：
Wee, Susan;Jagani, Zainab;Stegmeier, Frank
通讯作者：
Stegmeier, Frank
影响因子：
45.3
作者：
Goldberg, RM;Sargent, DJ;Alberts, SR
通讯作者：
Alberts, SR
影响因子：
--
作者：
Lee MS;Helms TL;Feng N;Gay J;Chang QE;Tian F;Wu JY;Toniatti C;Heffernan TP;Powis G;Kwong LN;Kopetz S
通讯作者：
Kopetz S
影响因子：
11.5
作者：
Migliardi, Giorgia;Sassi, Francesco;Bertotti, Andrea
通讯作者：
Bertotti, Andrea
DOI：
10.1158/1078-0432.ccr-13-1943
发表时间：
2014-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Guinney J;Ferté C;Dry J;McEwen R;Manceau G;Kao KJ;Chang KM;Bendtsen C;Hudson K;Huang E;Dougherty B;Ducreux M;Soria JC;Friend S;Derry J;Laurent-Puig P
通讯作者：
Laurent-Puig P