发现一种与对ALK酪氨酸激酶抑制反应相关的假定血液蛋白标志物。
Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition.
作者信息
Couëtoux du Tertre Mathilde, Marques Maud, McNamara Suzan, Gambaro Karen, Hoffert Cyrla, Tremblay Lise, Bouchard Nicole, Diaconescu Razvan, Blais Normand, Couture Christian, Pelsser Vincent, Wang Hangjun, McIntosh Laura, Hindie Valérie, Parent Stephane, Cortes Laetitia, Breton Yannick-André, Pottiez Gwenael, Croteau Pascal, Higenell Valerie, Izzi Luisa, Spatz Alan, Cohen Victor, Batist Gerald, Agulnik Jason
机构信息
Segal Cancer Centre, Jewish General Hospital, McGill University, Jewish General Hospital, 3755, Chemin Cote Ste-Catherine, Montreal, QC H3T1E2 Canada.
Exactis Innovation, Montréal, QC Canada.
出版信息
Clin Proteomics. 2020 Feb 7;17:5. doi: 10.1186/s12014-020-9269-6. eCollection 2020.
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. ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.
背景
间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制已成为ALK融合阳性非小细胞肺癌（NSCLC）患者临床管理的主要手段。尽管ALK突变能够可靠地预测对克唑替尼等ALK酪氨酸激酶抑制剂（TKIs）的反应可能性，但它们无法可靠地预测反应持续时间或内在/外在治疗耐药性。为了进一步优化个性化医疗在该适应症中的应用，本研究旨在识别ALK融合阳性NSCLC患者对克唑替尼的预后蛋白质组学生物标志物。
方法
在一项IV期试验中，对24例携带ALK融合的晚期NSCLC患者给予克唑替尼治疗，该试验包括治疗前采血。使用MRM-MS对327种蛋白质进行靶向蛋白质组学分析，以测量基线时（包括治疗前和治疗早期血样）的血浆水平，并评估潜在的临床关联。
结果
根据反应持续时间对患者进行分类：长期反应者[无进展生存期（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长期反应者和反应不佳者之间差异表达，包括二肽基肽酶4（DPP4）、原癌基因c-KIT（KIT）和层黏连蛋白（LUM）。接下来，使用机器学习算法，我们评估了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种蛋白质作为携带ALK融合的NSCLC患者对克唑替尼反应的基于血液的预后特征的潜在候选物。
结论
结合ALK突变，这种蛋白质组学特征的表达可能代表基于液体活检的NSCLC患者对克唑替尼长期反应的标志物。扩大反应持续时间预后生物标志物的应用可能会影响治疗选择、治疗顺序，以及潜在的替代或联合治疗需求。ClinicalTrials.gov，NCT02041468。2014年1月22日注册，https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1。
Zotero 插件