Background ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. Methods Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association. Results Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion. Conclusion In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy.Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.

中文翻译：

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发现与对 ALK 酪氨酸激酶抑制反应相关的推定的基于血液的蛋白质特征。

背景 ALK 酪氨酸激酶抑制已成为 ALK 融合阳性 NSCLC 患者临床管理的支柱。尽管 ALK 突变可以可靠地预测对 ALK 酪氨酸激酶抑制剂 (TKI) 如克唑替尼的反应可能性，但它们不能可靠地预测反应持续时间或内在/外在治疗耐药性。为了进一步完善个体化医疗在这一适应症中的应用，本研究旨在确定 ALK 融合阳性 NSCLC 患者对克唑替尼的预后蛋白质组生物标志物。方法 24 名携带 ALK 融合的晚期 NSCLC 患者在一项 IV 期试验中接受克唑替尼治疗，该试验包括治疗前的血液取样。使用 MRM-MS 的 327 种蛋白质的靶向蛋白质组学用于测量基线时的血浆水平（包括治疗前和早期治疗的血液样本）并评估潜在的临床关联。结果 患者按反应持续时间分类：长期反应者 [PFS ≥ 24 个月 (n = 7)]、正常反应者 [3 < PFS < 24 个月 (n = 10)] 和反应不佳者 [PFS ≤ 3 个月 (n = 5)]。几种蛋白质被鉴定为在长期反应者和不良反应者之间差异表达，包括 DPP4、KIT 和 LUM。接下来，我们使用机器学习算法评估了 40 种蛋白质的分类潜力。最后，通过整合不同的分析方法，我们选择了 22 种蛋白质作为潜在的候选蛋白，作为 ALK 融合的 NSCLC 患者对克唑替尼反应的基于血液的预后特征。结论 结合 ALK 突变，这种蛋白质组学特征的表达可能代表 NSCLC 中克唑替尼长期反应的基于液体活检的标志物。扩大反应持续时间的预后生物标志物的效用可能会影响治疗选择、治疗顺序，以及可能需要替代或联合治疗。试验注册 ClinicalTrials.gov，NCT02041468。2014 年 1 月 22 日注册，https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1。并可能需要替代或联合治疗。试验注册 ClinicalTrials.gov，NCT02041468。2014 年 1 月 22 日注册，https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1。并可能需要替代或联合治疗。试验注册 ClinicalTrials.gov，NCT02041468。2014 年 1 月 22 日注册，https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1。