Activation of the PI3K/AKT signaling pathway by ARNTL2 enhances cellular glycolysis and sensitizes pancreatic adenocarcinoma to erlotinib

作者：Weiyu Ge, Y Wang, Ming Quan, Tiebo Mao, Evelyne Yehudit Bischof, Haiyan Xu, Xiaofei Zhang, Shumin Li, Ming Yue, Jingyu Ma, Haiyan Yang, Lei Wang, Lei Wang, Zhengyuan Yu, Liwei Wang, Liwei Wang, Jiujie Cui · 发表于：Molecular Cancer · 年份：2024 · DOI：10.1186/s12943-024-01965-5 · 被引用次数：40 · 研究领域：Pancreatic and Hepatic Oncology Research、PI3K/AKT/mTOR signaling in cancer、Lung Cancer Research Studies

BACKGROUND: 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. METHODS AND RESULTS: 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 pati...