Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Rare Tumor Initiative, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Mol Cancer Res. 2023 Apr 1;21(4):316-331. doi: 10.1158/1541-7786.MCR-21-1036.
Combinatorial molecular therapy in pancreatic ductal adenocarcinoma (PDAC) has yielded largely disappointing results in clinical testing to-date as a multitude of adaptive resistance mechanisms is making selection of patients via molecular markers that capture essential, intersecting signaling routes challenging. Here, we report the scaffolding protein connector enhancer of kinase suppressor of Ras 1 (CNKSR1) as mediator of resistance to MAPK (MEK) inhibition. MEK inhibition in CNKSR1high cancer cells induces translocation of CNKSR1 to the plasma membrane where the scaffolding protein interacts with and stabilizes the phosphorylated form of AKT. CNKSR1-mediated AKT activation following MEK inhibition was associated with increased cellular p-PRAS40 levels and reduced nuclear translocation and cellular levels of FoxO1, a negative regulator of AKT signaling. In clinical PDAC specimens, high cytoplasmatic CNKSR1 levels correlated with increased cellular phospho-AKT and mTOR levels. Pharmacological co-blockade of AKT and MEK ranked top in induced synergies with MEK inhibition in CNKSR1high pancreas cancer cells among other inhibitor combinations targeting known CNKSR1 signaling. In vivo, CNKSR1high pancreatic tumors treated with AKT and MEK inhibitors showed improved outcome in the combination arm compared with single-agent treatment, an effect not observed in CNKSR1low models.Our results identify CNKSR1 as regulator of adaptive resistance to MEK inhibition by promoting crosstalk to AKT signaling via a scaffolding function for the phosphorylated form of AKT. CNSKR1 expression might be a possible molecular marker to enrich patients for future AKT-MEK inhibitor precision medicine studies.
The CNKSR1 scaffold, identified within an RNAi screen as a novel mediator of resistance to MEK inhibition in pancreas cancer, connects the MAPK pathway and AKT signaling and may be adopted as a biomarker to select patients for combined MEK AKT blockade.
迄今为止，在胰腺导管腺癌 (PDAC) 的组合分子治疗的临床测试中产生了大量令人失望的结果，因为多种适应性抵抗机制使得通过捕获基本的、相交信号途径的分子标志物选择患者具有挑战性。在这里，我们报告连接蛋白激酶抑制剂 Ras 接头增强子 1 (CNKSR1) 作为 MAPK (MEK) 抑制耐药的介质。CNKSR1 高癌细胞中的 MEK 抑制诱导 CNKSR1 易位到质膜，其中支架蛋白与磷酸化形式的 AKT 相互作用并稳定其。MEK 抑制后 CNKSR1 介导的 AKT 激活与细胞内 p-PRAS40 水平增加以及 FoxO1 的核转位和细胞水平降低有关，FoxO1 是 AKT 信号的负调节剂。在临床 PDAC 标本中，高细胞质 CNKSR1 水平与细胞内磷酸化 AKT 和 mTOR 水平增加相关。在针对已知 CNKSR1 信号的其他抑制剂组合中，与 MEK 抑制相比，AKT 和 MEK 的药理学联合阻断在 CNKSR1 高胰腺癌细胞中排名最高，诱导协同作用。在体内，用 AKT 和 MEK 抑制剂治疗的 CNKSR1 高胰腺肿瘤在联合治疗组中表现出比单药治疗更好的结果，而在 CNKSR1 低模型中则没有观察到这种效果。我们的结果表明，CNKSR1 通过促进 AKT 信号的串扰作为 AKT 磷酸化形式的支架功能，成为 MEK 抑制适应性抵抗的调节剂。CNSKR1 表达可能是一种可能的分子标志物，可丰富未来 AKT-MEK 抑制剂精准医学研究的患者。
在 RNAi 筛选中鉴定出的 CNKSR1 支架作为胰腺癌细胞中 MEK 抑制耐药的新型介质，连接 MAPK 途径和 AKT 信号，可作为生物标志物用于选择接受 MEK AKT 阻断联合治疗的患者。
