Department of Abdominal Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China.
Cell Death Differ. 2019 Nov;26(11):2400-2415. doi: 10.1038/s41418-019-0309-6. Epub 2019 Mar 4.
Tumours manage to survive the ablation of mutant KRAS, despite the development of KRAS-targeted drugs. Here we describe that inhibition of mutant KRAS promotes MEK nuclear localization as an alternative mechanism of KRAS-targeted drugs resistance. Tissue microarray analysis in colon tumours shows that aberrant MEK nuclear localization is closely related to YAP levels and tumour malignancy. MEK nuclear localization could sequester β-TrCP from cytoplasmic inactive YAP, then stabilizing YAP. Mutant KRAS restrains MEK within the cytoplasm via IQGAP1, inhibiting MEK nuclear translocation. Trametinib, an allosteric MEK inhibitor, could prevent MEK nuclear localization and subsequently promote YAP degradation. In vitro and in vivo results suggests that inhibition of MEK nuclear localization by trametinib synergizes with KRAS knockdown or deltarasin treatment in suppressing the viability of KRAS mutant colon cancer cells. Our study provides new insights into the mechanisms of resistance to KRAS ablation, and suggests novel strategies for the treatment of KRAS-mutant colon cancers.
肿瘤能够在 KRAS 突变体消融后存活下来，尽管已经开发出了 KRAS 靶向药物。在这里，我们描述了抑制 KRAS 突变体可促进 MEK 核定位，这是 KRAS 靶向药物耐药的另一种机制。结肠肿瘤的组织微阵列分析表明，异常的 MEK 核定位与 YAP 水平和肿瘤恶性程度密切相关。MEK 核定位可以将细胞质中无活性的 YAP 与 β-TrCP 隔离，从而稳定 YAP。突变型 KRAS 通过 IQGAP1 将 MEK 限制在细胞质中，抑制 MEK 核易位。MEK 的变构抑制剂 trametinib 可以防止 MEK 核定位，并随后促进 YAP 的降解。体外和体内结果表明，trametinib 通过抑制 MEK 核定位与 KRAS 敲低或 deltarasin 联合治疗，可抑制 KRAS 突变型结肠癌细胞的活力。我们的研究为 KRAS 消融耐药的机制提供了新的见解，并为治疗 KRAS 突变型结肠癌提供了新的策略。
