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m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
Journal of Hematology & Oncology ( IF 28.5 ) Pub Date : 2021-11-10 , DOI: 10.1186/s13045-021-01173-4 Zhihui Zhang 1 , Chaoqi Zhang 1 , Zhaoyang Yang 2 , Guochao Zhang 1 , Peng Wu 1 , Yuejun Luo 1 , Qingpeng Zeng 1 , Lide Wang 1 , Qi Xue 1 , Yi Zhang 3 , Nan Sun 1 , Jie He 1
Journal of Hematology & Oncology ( IF 28.5 ) Pub Date : 2021-11-10 , DOI: 10.1186/s13045-021-01173-4 Zhihui Zhang 1 , Chaoqi Zhang 1 , Zhaoyang Yang 2 , Guochao Zhang 1 , Peng Wu 1 , Yuejun Luo 1 , Qingpeng Zeng 1 , Lide Wang 1 , Qi Xue 1 , Yi Zhang 3 , Nan Sun 1 , Jie He 1
Affiliation
Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N6-methyladenosine (m6A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m6A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m6A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m6A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m6A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m6A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators—ZCCHC4, G3BP1, and RBMX—may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m6A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m6A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC.
中文翻译:
m6A 调节剂作为化疗益处的预测生物标志物和克服小细胞肺癌化疗耐药的潜在治疗靶点
小细胞肺癌 (SCLC) 是一种毁灭性的肺癌亚型,几乎没有治疗选择。尽管免疫疗法问世,铂类化疗仍然是小细胞肺癌不可替代的一线疗法。然而,大多数患者总是会出现耐药性,并且结果是异质的。因此,迫切需要临床上可行的分类策略和克服化疗耐药的潜在治疗靶点。N6-甲基腺苷(m6A)是一种新的表观遗传决定因素,参与肿瘤进展和耐药性。然而,对于 SCLC 中的 m6A 修饰几乎一无所知。在这里,我们评估了来自三个不同队列接受化疗的患者的 200 个 SCLC 样本,包括一个包含 71 个具有 qPCR 数据的病例的验证队列和一个包含 79 个具有免疫组织化学数据的病例的独立队列(量化为 H 分数)。我们系统地描述了 m6A 调节剂在 SCLC 患者化疗后的预测前景。使用 LASSO Cox 模型,我们构建了一个基于七种调节剂(ZCCHC4、IGF2BP3、ALKBH5、YTHDF3、METTL5、G3BP1 和 RBMX)的化疗益处预测分类器(m6A 评分),随后在另外两个队列中验证了该分类器。时间依赖性 ROC 和 C 指数分析表明,与其他临床病理参数相比,m6A 评分对化疗获益具有更高的预测能力。多队列多变量分析显示,m6A 评分是影响多个队列生存获益的独立因素。我们的体外实验结果表明,三种调节剂——ZCCHC4、G3BP1 和 RBMX——可作为克服 SCLC 化学抗性的有希望的新治疗靶点。我们的研究结果首次证明了 m6A 调节剂对化疗益处的预测意义,以及它们作为克服 SCLC 患者化疗耐药性的治疗靶点的潜力。m6A 评分被发现是一种可靠的预后工具,可能有助于指导 SCLC 患者的化疗决策。以及它们作为克服 SCLC 患者化疗耐药性的治疗靶点的潜力。m6A 评分被发现是一种可靠的预后工具,可能有助于指导 SCLC 患者的化疗决策。以及它们作为克服 SCLC 患者化疗耐药性的治疗靶点的潜力。m6A 评分被发现是一种可靠的预后工具,可能有助于指导 SCLC 患者的化疗决策。
更新日期:2021-11-10
中文翻译:
m6A 调节剂作为化疗益处的预测生物标志物和克服小细胞肺癌化疗耐药的潜在治疗靶点
小细胞肺癌 (SCLC) 是一种毁灭性的肺癌亚型,几乎没有治疗选择。尽管免疫疗法问世,铂类化疗仍然是小细胞肺癌不可替代的一线疗法。然而,大多数患者总是会出现耐药性,并且结果是异质的。因此,迫切需要临床上可行的分类策略和克服化疗耐药的潜在治疗靶点。N6-甲基腺苷(m6A)是一种新的表观遗传决定因素,参与肿瘤进展和耐药性。然而,对于 SCLC 中的 m6A 修饰几乎一无所知。在这里,我们评估了来自三个不同队列接受化疗的患者的 200 个 SCLC 样本,包括一个包含 71 个具有 qPCR 数据的病例的验证队列和一个包含 79 个具有免疫组织化学数据的病例的独立队列(量化为 H 分数)。我们系统地描述了 m6A 调节剂在 SCLC 患者化疗后的预测前景。使用 LASSO Cox 模型,我们构建了一个基于七种调节剂(ZCCHC4、IGF2BP3、ALKBH5、YTHDF3、METTL5、G3BP1 和 RBMX)的化疗益处预测分类器(m6A 评分),随后在另外两个队列中验证了该分类器。时间依赖性 ROC 和 C 指数分析表明,与其他临床病理参数相比,m6A 评分对化疗获益具有更高的预测能力。多队列多变量分析显示,m6A 评分是影响多个队列生存获益的独立因素。我们的体外实验结果表明,三种调节剂——ZCCHC4、G3BP1 和 RBMX——可作为克服 SCLC 化学抗性的有希望的新治疗靶点。我们的研究结果首次证明了 m6A 调节剂对化疗益处的预测意义,以及它们作为克服 SCLC 患者化疗耐药性的治疗靶点的潜力。m6A 评分被发现是一种可靠的预后工具,可能有助于指导 SCLC 患者的化疗决策。以及它们作为克服 SCLC 患者化疗耐药性的治疗靶点的潜力。m6A 评分被发现是一种可靠的预后工具,可能有助于指导 SCLC 患者的化疗决策。以及它们作为克服 SCLC 患者化疗耐药性的治疗靶点的潜力。m6A 评分被发现是一种可靠的预后工具,可能有助于指导 SCLC 患者的化疗决策。