■药物基因组学对于个体化药物治疗至关重要,在精准医学决策中发挥着越来越重要的作用。然而,基于药物基因组学的分子亚型及其潜在的临床意义在肺腺癌(LUAD)中仍未被研究.
■总共从8个独立的队列中招募了2065个样本。药物基因组学数据由同时在混合物(PRISM)和癌症药物敏感性基因组学(GDSC)数据库中的相对抑制谱生成。进行多种生物信息学方法以鉴定基于药物基因组学的亚型并发现亚型特异性特性。
■发现了三种可重复的分子亚型,是独立的预后因素,与分期高度相关,生存状态,和公认的分子亚型。基于药物基因组学的亚型具有明显的分子特征:S-Ⅰ为炎性,增殖性,免疫逃避;S-Ⅱ是增殖和遗传驱动;S-Ⅲ是代谢和甲基化驱动。最后,我们的研究提供了亚型指导的个性化治疗策略:免疫检查点阻断剂(ICB),阿霉素,替比法尼,AZ628和AZD6244用于S-Ⅰ;顺铂,喜树碱,Roscovitine,和A.443654为S-Ⅱ;多西他赛,紫杉醇,长春瑞滨,和BIBW2992为S-III。
■我们提供了一种新的分子分类策略,并揭示了LUAD患者的三种基于药物基因组学的亚型,揭示了潜在的亚型相关和患者特异性治疗策略。
UNASSIGNED: Pharmacogenomics is crucial for individualized drug therapy and plays an increasingly vital role in precision medicine decision-making. However, pharmacogenomics-based molecular subtypes and their potential clinical significance remain primarily unexplored in lung adenocarcinoma (LUAD).
UNASSIGNED: A total of 2065 samples were recruited from eight independent cohorts. Pharmacogenomics data were generated from the profiling of relative inhibition simultaneously in mixtures (PRISM) and the genomics of drug sensitivity in cancer (GDSC) databases. Multiple bioinformatics approaches were performed to identify pharmacogenomics-based subtypes and find subtype-specific properties.
UNASSIGNED: Three reproducible molecular subtypes were found, which were independent prognostic factors and highly associated with stage, survival status, and accepted molecular subtypes. Pharmacogenomics-based subtypes had distinct molecular characteristics: S-Ⅰ was inflammatory, proliferative, and immune-evasion; S-Ⅱ was proliferative and genetics-driven; S-III was metabolic and methylation-driven. Finally, our study provided subtype-guided personalized treatment strategies: Immune checkpoint blockers (ICBs), doxorubicin, tipifarnib, AZ628, and AZD6244 were for S-Ⅰ; Cisplatin, camptothecin, roscovitine, and A.443654 were for S-Ⅱ; Docetaxel, paclitaxel, vinorelbine, and BIBW2992 were for S-III.
UNASSIGNED: We provided a novel molecular classification strategy and revealed three pharmacogenomics-based subtypes for LUAD patients, which uncovered potential subtype-related and patient-specific therapeutic strategies.