Pancreatic adenocarcinoma (PC) is an aggressive malignancy with limited treatment options. The poor prognosis primarily stems from late-stage diagnosis and when the disease has become therapeutically challenging. There is an urgent need to identify specific biomarkers for cancer subtyping and early detection to enhance both morbidity and mortality outcomes. The addition of the EGFR tyrosine kinase inhibitor (TKI), erlotinib, to gemcitabine chemotherapy for the first-line treatment of patients with advanced pancreatic cancer slightly improved outcomes. However, restricted clinical benefits may be linked to the absence of well-characterized criteria for stratification and dependable biomarkers for the prediction of treatment effectiveness. We examined the levels of various cancer hallmarks and identified glycolysis as the primary risk factor for overall survival in PC. Subsequently, we developed a glycolysis-related score (GRS) model to accurately distinguish PC patients with high GRS. Through in silico screening of 4398 compounds, we discovered that erlotinib had the strongest therapeutic benefits for high-GRS PC patients. Furthermore, we identified ARNTL2 as a novel prognostic biomarker and a predictive factor for erlotinib treatment responsiveness in patients with PC. Inhibition of ARNTL2 expression reduced the therapeutic efficacy, whereas increased expression of ARNTL2 improved PC cell sensitivity to erlotinib. Validation in vivo using patient-derived xenografts (PDX-PC) with varying ARNTL2 expression levels demonstrated that erlotinib monotherapy effectively halted tumor progression in PDX-PC models with high ARNTL2 expression. In contrast, PDX-PC models lacking ARNTL2 did not respond favorably to erlotinib treatment. Mechanistically, we demonstrated that the ARNTL2/E2F1 axis-mediated cellular glycolysis sensitizes PC cells to erlotinib treatment by activating the PI3K/AKT signaling pathway. Our investigations have identified ARNTL2 as a novel prognostic biomarker and predictive indicator of sensitivity. These results will help to identify erlotinib-responsive cases of PC and improve treatment outcomes. These findings contribute to the advancement of precision oncology, enabling more accurate and targeted therapeutic interventions.

中文翻译：

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ARNTL2 激活 PI3K/AKT 信号通路可增强细胞糖酵解并使胰腺腺癌对厄洛替尼敏感

胰腺癌（PC）是一种侵袭性恶性肿瘤，治疗选择有限。预后不良主要源于晚期诊断以及疾病在治疗上变得具有挑战性。迫切需要确定癌症亚型和早期检测的特定生物标志物，以提高发病率和死亡率。在吉西他滨化疗中添加 EGFR 酪氨酸激酶抑制剂 (TKI) 厄洛替尼作为晚期胰腺癌患者的一线治疗，结果略有改善。然而，临床获益有限可能与缺乏明确的分层标准和预测治疗效果的可靠生物标志物有关。我们检查了各种癌症标志的水平，并将糖酵解确定为 PC 总体生存的主要危险因素。随后，我们开发了糖酵解相关评分（GRS）模型来准确区分高GRS的PC患者。通过对 4398 种化合物进行计算机筛选，我们发现厄洛替尼对高 GRS PC 患者具有最强的治疗效果。此外，我们将 ARNTL2 确定为一种新型预后生物标志物和 PC 患者厄洛替尼治疗反应性的预测因素。抑制 ARNTL2 表达会降低治疗效果，而增加 ARNTL2 表达可提高 PC 细胞对厄洛替尼的敏感性。使用具有不同 ARNTL2 表达水平的患者来源的异种移植物 (PDX-PC) 进行的体内验证表明，厄洛替尼单一疗法可有效阻止具有高 ARNTL2 表达的 PDX-PC 模型中的肿瘤进展。相比之下，缺乏 ARNTL2 的 PDX-PC 模型对厄洛替尼治疗反应不佳。从机制上讲，我们证明 ARNTL2/E2F1 轴介导的细胞糖酵解通过激活 PI3K/AKT 信号通路使 PC 细胞对厄洛替尼治疗敏感。我们的研究已确定 ARNTL2 是一种新型预后生物标志物和敏感性预测指标。这些结果将有助于识别对厄洛替尼有反应的 PC 病例并改善治疗结果。这些发现有助于精准肿瘤学的进步，实现更准确、更有针对性的治疗干预。