Quantification of Tyrosine Phosphorylation and Kinase Expression in NSCLC

描述（由申请人提供）：靶向治疗，特别是通过激酶抑制，继续成为非小细胞肺癌（NSCLC）个性化治疗的一种方法。例如，表皮生长因子受体（EGFR）驱动突变的患者可以用厄洛替尼或其他靶向EGFR抑制剂治疗，以改善其预后。然而，许多肺癌患者（约50%）的肿瘤没有已知的致癌驱动突变；因此，他们的治疗选择是有限的。为了扩大这些患者的治疗药物库，将使用蛋白质磷酸化和激酶活性水平的定量测量来检查每个肿瘤中的主要信号通路，并将其与从同一肺叶切除的相应正常肺组织进行比较。液相色谱-多重反应监测质谱（LC-MRM）将用于监测260多个酪氨酸磷酸化肽，以生成磷酸化谱，并使用基于活性的蛋白质谱标记和亲和纯化160多个肽，以指示活性激酶的水平。在一起,

DESCRIPTION (provided by applicant): Targeted therapy, specifically through kinase inhibition, continues to emerge as a method for personalized therapy in non-small cell lung cancer (NSCLC). As an example, patients with driver mutations in the epidermal growth factor receptor (EGFR) can be treated with Erlotinib or other targeted EGFR inhibitors to improve their outcomes. However, many lung cancer patients (~50%) have tumors that do not have known oncogenic driver mutations; subsequently, their treatment options are limited. In order to expand the arsenal of therapeutic agents for these patients, quantitative measurements of protein phosphorylation and kinase activity levels will be used to examine the dominant signaling pathways in each tumor, when compared with the corresponding normal lung tissue resected from the same lobe of the lung. Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) will be used to monitor more than 260 tyrosine-phosphorylated peptides to generate phosphorylation profiles and more than 160 peptides labeled and affinity purified using activity-based protein profiling to indicate the levels of active kinases. Together, these data will be used to indicate activated pathways and infer hubs that can be disrupted using existing kinase inhibitors. This quantitative platform for patient assessment will seek options for treatment of NSCLC with no known driver mutations, with the ultimate goal of defining a small list of candidate biomarkers that can be tested in biopsies. The development of this systematic approach to explore signaling in lung cancer will also provide insights into the analysis of signaling networks with quantitative mass spectrometry and the clinical utility of LC-MRM.