Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma.
Quantitative In Vivo Analyses Reveal a Complex Pharmacogenomic Landscape in Lung Adenocarcinoma.
复制标题
定量体内分析揭示了肺腺癌中复杂的药物基因组学景观。
DOI：
10.1158/0008-5472.can-21-0716
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发表时间：
2021-09-01
期刊：
影响因子：
11.2
通讯作者：
Winslow MM
中科院分区：
文献类型：
--
作者：
Li C;Lin WY;Rizvi H;Cai H;McFarland CD;Rogers ZN;Yousefi M;Winters IP;Rudin CM;Petrov DA;Winslow MM
缺乏关于肿瘤基因型和治疗反应之间关系的知识仍然是有效使用癌症治疗的最关键差距之一。在这里，我们将一个多重和定量的实验平台与强大的统计方法相结合，以实现体内肺癌治疗反应的药物基因组学映射。基因型特异性治疗反应的复杂图谱发现，超过20%的可能相互作用显示出显著的耐药性或敏感性。确定了已知的和新的相互作用，其中一种相互作用，KEAP 1突变型肺肿瘤对铂治疗的耐药性，使用大型患者反应数据集进行了验证。这些结果突出了肿瘤抑制基因型对治疗反应的广泛影响，并定义了一种确定精确治疗决定因素的策略。
The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1 mutant lung tumors to platinum therapy, was validated using a large patient response dataset. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies.