Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea.
Cancer Research Institute, Seoul National University, Korea.
Mol Oncol. 2018 Aug;12(8):1398-1409. doi: 10.1002/1878-0261.12345. Epub 2018 Jul 11.
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.
虽然 MEK 阻断已被突出显示为一种有前途的抗肿瘤药物，但它在 KRAS 突变型结直肠癌（CRC）中的临床疗效不佳。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通路的激活，从而降低了单一 MEK 靶向治疗的有效性。在这里，我们研究了 KRAS CRC 对 MEK 抑制的耐药性的旁路机制。我们发现，具有 refametinib（MEK 抑制剂）的 KRAS 突变型 CRC 细胞诱导 MIF 分泌，导致 STAT3 和 MAPK 的激活。通过 siRNA 敲低 MIF 可恢复 KRAS 突变细胞对 refametinib 的敏感性。此外，与 refametinib 和 MIF 抑制剂 4-IPP 联合使用可有效降低 STAT3 和 MAPK 的活性，比单一药物治疗更有效。结果表明，通过抑制 MIF 激活，联合治疗对 refametinib 耐药细胞表现出协同的生长抑制作用。这些结果表明，MIF 诱导的 STAT3 和 MAPK 激活引发了对 refametinib 的内在耐药性。我们的研究结果为基于对 MEK 和 MIF 途径之间的串扰的理解的针对 KRAS 突变型结直肠癌的合理联合治疗策略提供了依据。
