舒林酸(K-80003)与纳布-紫杉醇和吉西他滨联合治疗耐药性胰腺癌

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Cheng-Ke Xie, Cheng-Yu Liao, Hong-Yi Lin, Yong-Ding Wu, Feng-Chun Lu, Xiao-Xiao Huang, Zu-Wei Wang, Ge Li, Cai-Feng Lin, Jian-Fei Hu, Yin-Hao Chen, Qiao-Wei Li, Li-Qun Chen, Hui-Xing Chen, Shi Chen
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引用次数: 0

摘要

纳布-紫杉醇联合吉西他滨(AG)方案是胰腺癌的主要化疗方案,但经常出现耐药性。目前,能否促进耐药病例的增敏是一个重要的临床问题,而传统药物的再利用是一种很有前景的策略。本研究旨在找出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。我们还旨在找到药物联合敏感性的可靠预测生物标志物。通过 RNA 测序,我们发现 PI3K/Akt 通路的异常激活在介导 AG 方案的耐药性方面起着核心作用。随后,通过对随机选择的AG耐药患者衍生类器官(PDO)和PDO异种移植模型进行内部和外部验证,我们首次发现经典抗炎药舒林酸K-80003(我们重点研究的PI3K/Akt通路抑制剂)促进了半数(14/28)AG耐药胰腺导管腺癌病例的增敏。通过RNA测序、多重免疫荧光染色和免疫组织化学实验,我们发现cFAM124A是舒林酸K-80003促进AG敏化的新型生物标记物。cFAM124A 作为致敏标志物的作用可通过以下机制来解释:cFAM124A 可增强酪蛋白酶 L 的 mRNA 表达和酪蛋白酶 L 酶的活性。这种双重效应刺激了 RXRα 的裂解,导致大量截短的 RXRα 出现,成为 K-80003 的直接靶标。因此,这一过程导致了 PI3K/Akt 通路的病理性激活。总之,我们的研究为耐药性胰腺癌患者提供了一种新的治疗策略和新的生物靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer
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.
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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