BACKGROUND Gastric cancer is among the most lethal human malignancies. Previous studies have identified molecular aberrations that constitute dynamic biological networks and genomic complexities of gastric tumors. However, the clinical translation of molecular-guided targeted therapy is hampered by challenges. Notably, solid tumors often harbor multiple genetic alterations, complicating the development of effective treatments. METHODS To address such challenges, we established a comprehensive dataset of molecularly annotated patient derivatives coupled with pharmacological profiles for 60 targeted agents to explore dynamic pharmacogenomic interactions in gastric cancers. RESULTS We identified lineage-specific drug sensitivities based on histopathological and molecular subclassification, including substantial sensitivities toward VEGFR and EGFR inhibition therapies in diffuse- and signet ring-type gastric tumors, respectively. We identified potential therapeutic opportunities for WNT pathway inhibitors in ALK-mutant tumors, a significant association between PIK3CA-E542K mutation and AZD5363 response, and transcriptome expression of RNF11 as a potential predictor of response to gefitinib. CONCLUSIONS Collectively, our results demonstrate the feasibility of drug screening combined with tumor molecular characterization to facilitate personalized therapeutic regimens for gastric tumors.

中文翻译：

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胃癌的全面药物基因组学表征。

背景技术胃癌是最致命的人类恶性肿瘤之一。先前的研究已经确定了构成动态生物网络和胃肿瘤基因组复杂性的分子像差。然而，挑战限制了分子引导靶向治疗的临床翻译。值得注意的是，实体瘤通常具有多种遗传改变，使有效治疗的开发复杂化。方法为了应对此类挑战，我们建立了分子注释患者衍生物的完整数据集，并结合了60种靶向药物的药理特性，以探索胃癌中动态药物基因组学相互作用。结果我们根据组织病理学和分子亚分类确定了特定于谱系的药物敏感性，包括分别对弥散型和印戒型胃肿瘤对VEGFR和EGFR抑制疗法的敏感性。我们确定了ALK突变肿瘤中WNT途径抑制剂的潜在治疗机会，PIK3CA-E542K突变与AZD5363反应之间的显着关联以及RNF11的转录组表达作为对吉非替尼反应的潜在预测指标。结论总体而言，我们的结果证明了药物筛选与肿瘤分子表征相结合以促进胃癌个性化治疗方案的可行性。PIK3CA-E542K突变与AZD5363反应之间的显着关联，以及RNF11的转录组表达作为对吉非替尼反应的潜在预测因子。结论总体而言，我们的结果证明了药物筛选与肿瘤分子表征相结合以促进胃癌个性化治疗方案的可行性。PIK3CA-E542K突变与AZD5363反应之间的显着关联，以及RNF11的转录组表达作为对吉非替尼反应的潜在预测因子。结论总体而言，我们的结果证明了药物筛选与肿瘤分子表征相结合以促进胃癌个性化治疗方案的可行性。