胰腺导管腺癌（PDAC）是最具侵袭性和致命性的恶性肿瘤之一，缺乏有效的治疗方法。 90% 以上的 PDAC 中发生的 KRAS 突变是 PDAC 的主要致癌驱动因素。 MAPK 信号通路在 KRAS 驱动的致癌信号传导中发挥着核心作用。然而，MAPK 通路的药物抑制剂在 KRAS 突变 PDAC 中反应不佳，因此迫切需要了解其背后的机制并寻求新的治疗解决方案。在此，我们利用由 800 种天然来源的生物活性化合物组成的库进行筛选，以确定能够使 KRAS 突变 PDAC 细胞对 MAPK 抑制敏感的天然产物。我们发现粉防己碱是一种天然双苄基异喹啉生物碱，在 PDAC 细胞和异种移植模型中与 MAPK 抑制剂表现出协同作用。从机制上讲，MAPK 通路的药理抑制对 TRAIL-死亡受体轴表现出双刃剑的影响，转录上调 TRAIL，但下调其激动性受体 DR4 和 DR5，这可能解释了 MAPK 抑制剂在 KRAS 突变 PDAC 中的有限治疗效果。令人感兴趣的是，粉防己碱通过削弱泛素化介导的蛋白质降解来稳定 DR4/DR5 蛋白，从而与 MAPK 抑制协同作用，诱导 KRAS 突变 PDAC 细胞凋亡。我们的研究结果确定了一种治疗 KRAS 突变 PDAC 的新组合方法，并强调了 TRAIL-DR4/DR5 轴在决定 KRAS 突变 PDAC 治疗结果中的作用。版权所有 © 2023 作者。由爱思唯尔有限公司出版。保留所有权利。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify natural products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.