Background & Aims

Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen.

Methods

We utilized organoid models, patient-derived xenografts (PDX), and genetically engineered mouse models (GEMM) in our study. Chromatin-Immunoprecipitation (Ch-IP), double luciferase assay, Co-immunoprecipitation (Co-IP), and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in PDX, PDOX, and KPC models.

Results

Through multi-strategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1α, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IκBα to SKP1, leading to enhanced ubiquitination and degradation of IκBα, which further activates the NF-κB pathway. The potential AVL9-targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC.

Conclusion

AVL9 expression is driven by HIF1α in PDAC. The physical interaction of AVL9, IκBα, and SKP1 provides a novel molecular mechanism for the abnormal activation of the NF-κB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.

中文翻译：

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缺氧和酸性肿瘤微环境驱动的 AVL9 通过 AVL9-IκBα-SKP1 复合物促进胰腺导管腺癌的化疗耐药

 背景和目标

吉西他滨联合白蛋白-紫杉醇 （AG） 是胰腺导管腺癌 （PDAC） 的重要治疗选择。然而，对化疗的反应相对较差，耐药性迅速发展。本研究的目的是探讨对 AG 的耐药机制并制定可以使 AG 方案敏感的策略。

 方法

我们在研究中使用了类器官模型、患者来源的异种移植物 （PDX） 和基因工程小鼠模型 （GEMM）。进行染色质免疫沉淀 （Ch-IP） 、双荧光素酶测定、免疫共沉淀 （Co-IP） 和 far-western blotting 分析以研究其机制。通过蛋白结构分析和分子对接分析鉴定出 AVL9 抑制剂，并在 PDX 、 PDOX 和 KPC 模型中验证了其疗效。

 结果

通过多策略筛选，我们确定 AVL9 是 PDAC 中 AG 耐药的关键靶点。其促肿瘤作用在我们的临床队列中得到证实。从机制上讲，HIF-1α 是一种缺氧相关的转录因子，驱动 AVL9 的表达。AVL9 充当促进 IκBα 与 SKP1 结合的支架，导致 IκBα 的泛素化和降解增强，从而进一步激活 NF-κB 通路。潜在的 AVL9 靶向抑制剂 Edotecarin 被证明可以逆转 PDAC 中的 AG 化疗耐药。

 结论

AVL9 表达受 PDAC 中 HIF1α 驱动。AVL9、IκBα 和 SKP1 的物理相互作用为 NF-κB 通路的异常激活提供了一种新的分子机制。因此，靶向 AVL9 的药物 Edotecarin 可能是一种有前途的治疗策略，可使 PDAC 对 AG 敏感。