PDF(Pubmed)
Abstract：
Cervical cancer remains a significant global public health concern, often exhibits cisplatin resistance in clinical settings. Hypoxia, a characteristic of cervical cancer, substantially contributes to cisplatin resistance. To evaluate the therapeutic efficacy of cisplatin in patients with cervical cancer and to identify potential effective drugs against cisplatin resistance, we established a hypoxia-inducible factor-1 (HIF-1)-related risk score (HRRS) model using clinical data from patients treated with cisplatin. Cox and LASSO regression analyses were used to stratify patient risks and prognosis. Through qRT-PCR, we validated nine potential prognostic HIF-1 genes that successfully predict cisplatin responsiveness in patients and cell lines. Subsequently, we identified fostamatinib, an FDA-approved spleen tyrosine kinase inhibitor, as a promising drug for targeting the HRRS-high group. We observed a positive correlation between the IC50 values of fostamatinib and HRRS in cervical cancer cell lines. Moreover, fostamatinib exhibited potent anticancer effects on high HRRS groups in vitro and in vivo. In summary, we developed a hypoxia-related gene signature that suggests cisplatin response prediction in cervical cancer and identified fostamatinib as a potential novel treatment approach for resistant cases.
摘要：
宫颈癌仍然是一个重要的全球公共卫生问题，在临床上经常表现出顺铂耐药。缺氧,宫颈癌的特征，在很大程度上有助于顺铂耐药。评估顺铂对宫颈癌患者的疗效，并确定潜在的有效抗顺铂耐药药物。我们使用顺铂治疗患者的临床数据建立了缺氧诱导因子-1(HIF-1)相关风险评分(HRRS)模型.Cox和LASSO回归分析用于对患者风险和预后进行分层。通过qRT-PCR,我们验证了能够成功预测患者和细胞系中顺铂反应性的9个潜在预后HIF-1基因.随后，我们发现了福他替尼,FDA批准的脾酪氨酸激酶抑制剂，作为靶向HRRS高组的有希望的药物。我们观察到宫颈癌细胞系中福司替尼的IC50值与HRRS之间呈正相关。此外，福司替尼在体外和体内对高HRRS组显示出有效的抗癌作用。总之,我们开发了一个缺氧相关基因标签,提示宫颈癌顺铂反应预测,并确定了福司替尼是耐药病例的潜在新治疗方法.
