Macrophage migration inhibitory factor promotes resistance to MEK blockade in KRAS mutant colorectal cancer cells.
Macrophage migration inhibitory factor promotes resistance to MEK blockade in KRAS mutant colorectal cancer cells.
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DOI：
10.1002/1878-0261.12345
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发表时间：
2018-08
影响因子：
6.6
通讯作者：
Kim TY
中科院分区：
文献类型：
--
作者：
Cheon SK;Kim HP;Park YL;Jang JE;Lim Y;Song SH;Han SW;Kim TY
尽管MEK阻断剂被认为是一种有前途的抗肿瘤药物，但其在KRAS突变型结直肠癌（CRC）中的临床疗效较差。已经描述了几种反馈系统，其中一种细胞内途径的抑制导致平行信号传导途径的激活，从而降低了单MEK靶向治疗的有效性。在这里，我们研究了KRAS CRC中对MEK抑制的抗性的旁路机制。我们发现，KRAS突变CRC细胞与refametinib，MEK抑制剂，诱导MIF分泌，并导致STAT 3和MAPK激活。通过siRNA敲低MIF恢复了KRAS突变细胞对瑞法美替尼的敏感性。此外，与瑞法美替尼和4-IPP（一种MIF抑制剂）联合使用，可有效降低STAT 3和MAPK的活性，超过单药治疗。因此，发现联合治疗通过抑制MIF活化对refametinib耐药细胞表现出协同生长抑制作用。这些结果表明，MIF诱导的STAT 3和MAPK激活诱发了对refametinib的内在耐药性。我们的研究结果提供了一个合理的组合策略，对KRAS突变结直肠癌的基础上，MEK和MIF途径之间的串扰的理解。
Although MEK blockade has been highlighted as a promising antitumor drug, it has poor clinical efficacy in KRAS mutant colorectal cancer (CRC). Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single‐MEK targeted therapies. Here, we investigated a bypass mechanism of resistance to MEK inhibition in KRAS CRC. We found that KRAS mutant CRC cells with refametinib, MEK inhibitor, induced MIF secretion and resulted in activation of STAT3 and MAPK. MIF knockdown by siRNA restored sensitivity to refametinib in KRAS mutant cells. In addition, combination with refametinib and 4‐IPP, a MIF inhibitor, effectively reduced the activity of STAT3 and MAPK, more than single‐agent treatment. As a result, combined therapy was found to exhibit a synergistic growth inhibitory effect against refametinib‐resistant cells by inhibition of MIF activation. These results reveal that MIF‐induced STAT3 and MAPK activation evoked an intrinsic resistance to refametinib. Our results provide the basis for a rational combination strategy against KRAS mutant colorectal cancers, predicated on the understanding of cross talk between the MEK and MIF pathways.
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影响因子：
3.8
作者：
Chang Q;Chapman MS;Miner JN;Hedley DW
通讯作者：
Hedley DW
DOI：
10.1158/1078-0432.ccr-14-2124
发表时间：
2015-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arcila ME;Drilon A;Sylvester BE;Lovly CM;Borsu L;Reva B;Kris MG;Solit DB;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
28.5
作者：
Akinleye A;Furqan M;Mukhi N;Ravella P;Liu D
通讯作者：
Liu D
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
3.7
作者：
Kim HP;Yoon YK;Kim JW;Han SW;Hur HS;Park J;Lee JH;Oh DY;Im SA;Bang YJ;Kim TY
通讯作者：
Kim TY