Sulindac (K-80003) with nab-paclitaxel and gemcitabine overcomes drug-resistant pancreatic cancer

吉西他滨 紫杉醇 苏林达克 药品 胰腺癌 生物 紫杉醇 癌症 抗药性 肿瘤科 脱氧胞苷 内科学 癌症研究 药理学 医学 非甾体 微生物学
作者
Chengke Xie,Cheng‐Yu Liao,Hong-Yi Lin,Yongding Wu,Feng-Chun Lu,Xiaoxiao Huang,Zuwei Wang,Ge Li,Cai‐Feng Lin,Jianfei Hu,Yinhao Chen,Qiaowei Li,Li‐Qun Chen,Huixing Chen,Shi Chen
出处
期刊:Molecular Cancer [Springer Nature]
卷期号:23 (1)
标识
DOI:10.1186/s12943-024-02128-2
摘要

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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