Országhová Zuzana, Kalavska Katarina, Mego Michal, Chovanec Michal
2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia.
Translational Research Unit, Faculty of Medicine, Comenius University and National Cancer Institute, 833 10 Bratislava, Slovakia.
Biomedicines. 2022 Apr 22;10(5):972. doi: 10.3390/biomedicines10050972.
Testicular germ cell tumors (GCTs) are highly curable malignancies. Excellent survival rates in patients with metastatic disease can be attributed to the exceptional sensitivity of GCTs to cisplatin-based chemotherapy. This hypersensitivity is probably related to alterations in the DNA repair of cisplatin-induced DNA damage, and an excessive apoptotic response. However, chemotherapy fails due to the development of cisplatin resistance in a proportion of patients. The molecular basis of this resistance appears to be multifactorial. Tracking the mechanisms of cisplatin resistance in GCTs, multiple molecules have been identified as potential therapeutic targets. A variety of therapeutic agents have been evaluated in preclinical and clinical studies. These include different chemotherapeutics, targeted therapies, such as tyrosine kinase inhibitors, mTOR inhibitors, PARP inhibitors, CDK inhibitors, and anti-CD30 therapy, as well as immune-checkpoint inhibitors, epigenetic therapy, and others. These therapeutics have been used as single agents or in combination with cisplatin. Some of them have shown promising in vitro activity in overcoming cisplatin resistance, but have not been effective in clinical trials in refractory GCT patients. This review provides a summary of current knowledge about the molecular mechanisms of cisplatin sensitivity and resistance in GCTs and outlines possible therapeutic approaches that seek to overcome this chemoresistance.
睾丸生殖细胞肿瘤（GCTs）是高度可治愈的恶性肿瘤。转移性疾病患者的高生存率可归因于GCTs对基于顺铂的化疗具有极高的敏感性。这种超敏反应可能与顺铂诱导的DNA损伤的DNA修复改变以及过度的凋亡反应有关。然而，一部分患者会因顺铂耐药的产生而导致化疗失败。这种耐药的分子基础似乎是多因素的。追踪GCTs中顺铂耐药的机制，已鉴定出多种分子作为潜在的治疗靶点。在临床前和临床研究中已评估了多种治疗药物。这些药物包括不同的化疗药物、靶向治疗，如酪氨酸激酶抑制剂、mTOR抑制剂、PARP抑制剂、CDK抑制剂和抗CD30治疗，以及免疫检查点抑制剂、表观遗传治疗等。这些治疗药物已被用作单一药物或与顺铂联合使用。其中一些药物在克服顺铂耐药方面已显示出有前景的体外活性，但在难治性GCT患者的临床试验中尚未取得成效。本综述总结了目前关于GCTs中顺铂敏感性和耐药性分子机制的知识，并概述了旨在克服这种化疗耐药性的可能治疗方法。
