Overcoming Chemotherapy Resistance in Germ Cell Tumors

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 cisplatinbased 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.