Cisplatin Resistance in Testicular Germ Cell Tumors: Current Challenges from Various Perspectives

Abstract

Testicular germ cell tumors share a marked sensitivity to cisplatin, contributing to their overall good prognosis. However, a subset of patients develop resistance to platinum-based treatments, by still-elusive mechanisms, experiencing poor quality of life due to multiple (often ineffective) interventions and, eventually, dying from disease. Currently, there is a lack of defined treatment opportunities for these patients that tackle the mechanism(s) underlying the emergence of resistance. Herein, we aim to provide a multifaceted overview of cisplatin resistance in testicular germ cell tumors, from the clinical perspective, to the pathobiology (including mechanisms contributing to induction of the resistant phenotype), to experimental models available for studying this occurrence. We provide a systematic summary of pre-target, on-target, post-target, and off-target mechanisms putatively involved in cisplatin resistance, providing data from preclinical studies and from those attempting validation in clinical samples, including those exploring specific alterations as therapeutic targets, some of them included in ongoing clinical trials. We briefly discuss the specificities of resistance related to teratoma (differentiated) phenotype, including the phenomena of growing teratoma syndrome and development of somatic-type malignancy. Cisplatin resistance is most likely multifactorial, and a combination of therapeutic strategies will most likely produce the best clinical benefit.

Between a Rock and a Hard Place: An Epigenetic-Centric View of Testicular Germ Cell Tumors

“…Hence there is a strong rationale to develop alternative and cisplatin-sparing therapies for TGCTs. Similar to etiology and initiation, the mechanisms responsible for TGCT chemosensitivity and resistance have been elusive and appear for the most part to be independent of acquired genetic mutations or alterations [ 29 , 80 , 81 , 82 ]. In this section we briefly review traditional mechanisms proposed to account for TGCT chemosensitivity and resistance.…”

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

“…These cancers have an excellent prognosis, however, without adjuvant treatment, approximately 30% of non-seminomatous germ cell tumors (NSGCT) and 15% of seminomatous lesions relapse [ 1 ]. Platinum-based chemotherapy has improved the survival rate up to 90%, even though a percentage of patients still develop chemo-resistance, and a subset of them die due to disease progression [ 2 , 3 ]. Moreover, it is fair to highlight that adjuvant chemotherapy is associated with detrimental platinum-associated side effects [ 4 , 5 ], and this evidence is particularly relevant considering the young age of the patients at the onset of the disease.…”

“…Moreover, it is fair to highlight that adjuvant chemotherapy is associated with detrimental platinum-associated side effects [ 4 , 5 ], and this evidence is particularly relevant considering the young age of the patients at the onset of the disease. For these reasons, in the last decade, there have been efforts to find alternative therapeutic strategies [ 3 ] in order to achieve the goal of further improving the clinical outcome and, at the same time, minimizing therapy-related toxicity.…”

“…The investigation of the molecular features of TGCTs would help in identifying novel therapeutic targets that in turn could improve treatment outcomes, contributing to the development of a more personalized therapy. However, the exploration of possible second-generation therapies in pre-clinical studies is still limited [ 3 , 6 ].…”

Differential gene expression in cisplatin-resistant and -sensitive testicular germ cell tumor cell lines

“…The relapsed patients may be cured by salvage chemotherapy. Despite excellent treatment outcome, approximately 5% of patients do not respond even to salvage chemotherapy and die due to an adverse treatment response or develop chemoresistance [ 5 – 7 ].…”