Department of Medicine, Hematology/Oncology, Goethe University School of Medicine, Frankfurt, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
Proteomics. 2021 May;21(10):e2000283. doi: 10.1002/pmic.202000283. Epub 2021 Apr 10.
Kinase fusions are considered oncogenic drivers in numerous types of cancer. In lung adenocarcinoma 5-10% of patients harbor kinase fusions. The most frequently detected kinase fusion involves the Anaplastic Lymphoma Kinase (ALK) and Echinoderm Microtubule-associated protein-Like 4 (EML4). In addition, oncogenic kinase fusions involving the tyrosine kinases RET and ROS1 are found in smaller subsets of patients. In this study, we employed quantitative mass spectrometry-based phosphoproteomics to define the cellular tyrosine phosphorylation patterns induced by different oncogenic kinase fusions identified in patients with lung adenocarcinoma. We show that exogenous expression of the kinase fusions in HEK 293T cells leads to widespread tyrosine phosphorylation. Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1, and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.
激酶融合被认为是多种类型癌症的致癌驱动因素。在肺腺癌中，5-10%的患者存在激酶融合。最常检测到的激酶融合涉及间变性淋巴瘤激酶 (ALK) 和棘皮微管相关蛋白样 4 (EML4)。此外，较小部分的患者存在涉及酪氨酸激酶 RET 和 ROS1 的致癌性激酶融合。在这项研究中，我们采用基于定量质谱的磷酸化蛋白质组学来定义在肺腺癌患者中鉴定出的不同致癌性激酶融合所诱导的细胞酪氨酸磷酸化模式。我们表明，在 HEK 293T 细胞中外源表达激酶融合会导致广泛的酪氨酸磷酸化。对不同激酶融合的直接比较表明，是激酶部分而不是融合伴侣主要决定了磷酸化模式。ALK、ROS1 和 RET 融合之间的酪氨酸磷酸化模式不同，表明这些激酶诱导的致癌信号涉及不同细胞过程的调节。
