The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance’s core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.

中文翻译：

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Sulindac (K-80003) 与白蛋白结合型紫杉醇和吉西他滨一起克服了耐药性胰腺癌


白蛋白结合型紫杉醇联合吉西他滨（AG）方案是胰腺癌的主要化疗方案，但常发生耐药。目前，促进耐药病例致敏的能力是一个重要的临床问题，而重新利用常规药物的策略是一个有前途的策略。本研究旨在寻找一种针对化疗耐药核心信号通路的经典药物，并将其与 AG 方案相结合以增强化疗敏感性。我们还旨在寻找药物组合敏感性的可靠预测生物标志物。通过 RNA 测序，我们发现异常 PI3K/Akt 通路激活在介导 AG 方案耐药性中发挥着核心作用。随后，通过随机选取的AG耐药患者源性类器官（PDO）和PDO异种移植模型的内部和外部验证，我们首次发现经典抗炎药物舒林酸K-80003，一种PI3K/Akt抑制剂我们关注的途径促进了一半（14/28）AG 耐药胰腺导管腺癌病例的致敏。通过 RNA 测序、多重免疫荧光染色和免疫组织化学实验，我们确定 cFAM124A 是舒林酸 K-80003 促进 AG 致敏的新型生物标志物。它作为致敏标记物的作用通过以下机制来解释：cFAM124A 增强组织蛋白酶 L 的 mRNA 表达和组织蛋白酶 L 酶的活性。这种双重效应刺激 RXRα 的裂解，导致大量截短的 RXRα，成为 K-80003 的直接靶点。因此，该过程导致 PI3K/Akt 通路的病理激活。 总之，我们的研究为耐药胰腺癌患者提供了新的治疗策略和新的生物学靶点。