Effective therapies for pancreatic ductal adenocarcinoma (PDAC) have been largely elusive. Here, we perform Multiplexed kinase Inhibitor Bead Mass Spectrometry on 102 patient derived xenografts derived from 14 unique primary PDAC to define the tumor-intrinsic kinome landscape. Our findings uncover three kinome subgroups making up two tumor-intrinsic kinome subtypes that we call kinotypes. The kinotypes show enrichment of different kinase classes and recapitulate previously described molecular subtypes, basal-like and classical. The kinotype characterizing basal-like tumors shows enrichment of receptor tyrosine kinases, whereas the kinotype characterizing classical tumors is enriched in understudied kinases involved in Wnt signaling and immune pathways. We validate our findings in two clinical trials and show that only patients with basal-like tumors derive significant benefit from EGFR inhibitors. Our results provide a comprehensive tumor-intrinsic kinome landscape of PDAC that strongly supports actionable kinotype specific kinase targets and provides a roadmap for kinase inhibitor therapy in PDAC.

中文翻译：

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胰腺癌的肿瘤-内源性激酶组景观揭示了新的治疗方法


胰腺导管腺癌 （PDAC） 的有效疗法在很大程度上难以捉摸。在这里，我们对来自 14 个独特原发性 PDAC 的 102 个患者来源的异种移植物进行多重激酶抑制剂珠质谱分析，以定义肿瘤内在激酶组景观。我们的研究结果揭示了三个激酶组亚组，构成了两个我们称为激酶型的肿瘤内在激酶组亚型。基因型显示不同激酶类别的富集，并概括了先前描述的分子亚型，基础样和经典。表征基底样肿瘤的激酶型显示受体酪氨酸激酶的富集，而表征经典肿瘤的激酶激酶的激酶型富集于参与 Wnt 信号传导和免疫通路的研究不足的激酶。我们在两项临床试验中验证了我们的发现，并表明只有基底样肿瘤患者才能从 EGFR 抑制剂中获得显着益处。我们的结果提供了 PDAC 的全面肿瘤内在激酶组景观，强烈支持可操作的激酶型特异性激酶靶点，并为 PDAC 中的激酶抑制剂治疗提供了路线图。