Feng Yi, Li Caichen, Cheng Bo, Chen Ying, Chen Peiling, Wang Zixun, Zheng Xiangyuan, He Juan, Zhu Feng, Wang Wei, Liang Wenhua
Dpartment of Thoracic Surgery and Oncology, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Guangzhou Institute of Respiratory Health, Guangzhou, China.
Transl Lung Cancer Res. 2024 Aug 31;13(8):1780-1793. doi: 10.21037/tlcr-24-65. Epub 2024 Aug 28.
Lung cancer is responsible for most cancer-related deaths, and non-small cell lung cancer (NSCLC) accounts for the majority of cases. Targeted therapy has made promising advancements in systemic treatment for NSCLC over the last two decades, but inadequate drug targets with clinically proven survival benefits limit its universal application in clinical practice compared to chemotherapy and immunotherapy. There is an urgent need to explore new drug targets to expand the beneficiary group. This study aims to identify druggable genes and to predict the efficacy and prognostic value of the corresponding targeted drugs in NSCLC.
Two-sample mendelian randomization (MR) of druggable genes was performed to predict the efficacy of their corresponding targeted therapy for NSCLC. Subsequent sensitivity analyses were performed to assess potential confounders. Accessible RNA sequencing data were incorporated for subsequent verifications, and Kaplan-Meier survival curves of different gene expressions were used to explore the prognostic value of candidate druggable genes.
MR screening encompassing 4,863 expression quantitative trait loci (eQTL) and 1,072 protein quantitative trait loci (pQTL, with 453 proteins overlapping) were performed. Seven candidate druggable genes were identified, including , , and for lung adenocarcinoma, and , and for lung squamous cell carcinoma. The results were validated by further transcriptomic investigations.
Drugs targeting genetically supported genomes are considerably more likely to yield promising efficacy and succeed in clinical trials. We provide compelling genetic evidence to prioritize drug development for NSCLC.
肺癌是导致大多数癌症相关死亡的原因，非小细胞肺癌（NSCLC）占大多数病例。在过去二十年中，靶向治疗在NSCLC的全身治疗方面取得了有前景的进展，但与化疗和免疫疗法相比，具有临床证实生存益处的药物靶点不足限制了其在临床实践中的广泛应用。迫切需要探索新的药物靶点以扩大受益群体。本研究旨在鉴定可成药基因，并预测相应靶向药物在NSCLC中的疗效和预后价值。
对可成药基因进行两样本孟德尔随机化（MR）以预测其相应靶向治疗对NSCLC的疗效。随后进行敏感性分析以评估潜在混杂因素。纳入可获取的RNA测序数据进行后续验证，并使用不同基因表达的Kaplan-Meier生存曲线来探索候选可成药基因的预后价值。
进行了涵盖4863个表达数量性状位点（eQTL）和1072个蛋白质数量性状位点（pQTL，其中453种蛋白质重叠）的MR筛选。鉴定出7个候选可成药基因，包括肺腺癌的[具体基因1]、[具体基因2]、[具体基因3]和[具体基因4]，以及肺鳞状细胞癌的[具体基因5]、[具体基因6]和[具体基因7]。结果通过进一步的转录组学研究得到验证。
靶向基因支持基因组的药物更有可能产生有前景的疗效并在临床试验中取得成功。我们提供了令人信服的遗传证据，以优先开展NSCLC的药物研发。
