Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China.
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing 100021, China.
Lung Cancer. 2024 Mar;189:107503. doi: 10.1016/j.lungcan.2024.107503. Epub 2024 Feb 9.
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) has demonstrated remarkable therapeutic effects in ALK-positive non-small cell lung cancer (NSCLC) patients. Identifying prognostic biomarkers can enhance the clinical efficacy of relapsed or refractory patients.
We profiled 737 plasma proteins from 159 pre-treatment and on-treatment plasma samples of 63 ALK-positive NSCLC patients using data-independent acquisition-mass spectrometry (DIA-MS). The consensus clustering algorithm was used to identify subtypes with distinct biological features. A plasma-based prognostic model was constructed using the LASSO-Cox method. We performed the Mfuzz analysis to classify the patterns of longitudinal changes in plasma proteins during treatment. 52 baseline plasma samples from another independent ALK-TKI treatment cohort were collected to validate the potential prognostic markers using ELISA.
We identified three subtypes of ALK-positive NSCLC with distinct biological features and clinical efficacy. Patients in subgroup 1 exhibited activated humoral immunity and inflammatory responses, increased expression of positive acute-phase response proteins, and the worst prognosis. Then we constructed and verified a prognostic model that predicts the efficacy of ALK-TKI therapy using the expression levels of five plasma proteins (SERPINA4, ATRN, APOA4, TF, and MYOC) at baseline. Next, we explored the longitudinal changes in plasma protein expression during treatment and identified four distinct change patterns (Clusters 1-4). The longitudinal changes of acute-phase proteins during treatment can reflect the treatment status and tumor progression of patients. Finally, we validated the prognostic efficacy of baseline plasma CRP, SAA1, AHSG, SERPINA4, and TF in another independent NSCLC cohort undergoing ALK-TKI treatment.
This study contributes to the search for prognostic and drug-resistance biomarkers in plasma samples for ALK-TKI therapy and provides new insights into the mechanism of drug resistance and the selection of follow-up treatment.
间变性淋巴瘤激酶-酪氨酸激酶抑制剂（ALK-TKIs）在 ALK 阳性非小细胞肺癌（NSCLC）患者中显示出显著的治疗效果。确定预后生物标志物可以提高复发或耐药患者的临床疗效。
我们使用数据非依赖性采集-质谱（DIA-MS）技术对 63 例 ALK 阳性 NSCLC 患者的 159 个治疗前和治疗中血浆样本中的 737 种血浆蛋白进行了分析。使用共识聚类算法识别具有不同生物学特征的亚型。使用 LASSO-Cox 方法构建了基于血浆的预后模型。我们进行了 Mfuzz 分析，以分类治疗期间血浆蛋白纵向变化的模式。收集了另一个独立的 ALK-TKI 治疗队列的 52 个基线血浆样本，使用 ELISA 验证潜在的预后标志物。
我们鉴定了具有不同生物学特征和临床疗效的三种 ALK 阳性 NSCLC 亚型。亚组 1 患者表现出激活的体液免疫和炎症反应、阳性急性期反应蛋白表达增加以及最差的预后。然后，我们构建并验证了一个预后模型，该模型使用基线时 5 种血浆蛋白（SERPINA4、ATRN、APOA4、TF 和 MYOC）的表达水平预测 ALK-TKI 治疗的疗效。接下来，我们探讨了治疗期间血浆蛋白表达的纵向变化，并确定了四种不同的变化模式（Cluster 1-4）。治疗期间急性期蛋白的纵向变化可以反映患者的治疗状态和肿瘤进展。最后，我们在另一个接受 ALK-TKI 治疗的 NSCLC 队列中验证了基线血浆 CRP、SAA1、AHSG、SERPINA4 和 TF 的预后疗效。
本研究有助于寻找 ALK-TKI 治疗的血浆样本中的预后和耐药生物标志物，并为药物耐药机制和后续治疗选择提供了新的见解。
