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Review
. 2024 Nov 29:15:1480417.
doi: 10.3389/fgene.2024.1480417. eCollection 2024.

PARP inhibitors in testicular germ cell tumors: what we know and what we are looking for

Sara Parola  1 , Christoph Oing  2 , Pasquale Rescigno  2 , Salvatore Feliciano  1 , Francesca Carlino  1 , Luca Pompella  1 , Antonella Lucia Marretta  1 , Irene De Santo  1 , Martina Viggiani  3 , Margherita Muratore  4 , Bianca Arianna Facchini  5 , Jessica Orefice  5 , Eleonora Cioli  5 , Francesca Sparano  6 , Domenico Mallardo  6 , Ugo De Giorgi  4 , Giovannella Palmieri  7 , Paolo Antonio Ascierto  6 , Margaret Ottaviano  6
Affiliations
Review

PARP inhibitors in testicular germ cell tumors: what we know and what we are looking for

Sara Parola et al. Front Genet. .

Abstract

Testicular germ cell tumors (TGCTs), the most common malignancies affecting young men, are characterized by high sensitivity to cisplatin-based chemotherapy, which leads to high cure rates even in metastatic disease. However, approximately 30% of patients with metastatic TGCTs relapse after first-line treatment and those who can be defined as platinum-refractory patients face a very dismal prognosis with only limited chemotherapy-based treatment options and an overall survival of few months. Hence, to understand the mechanisms underlying cisplatin resistance is crucial for developing new treatment strategies. This narrative review explores the potential role of PARP inhibitors (PARPis) in overcoming cisplatin resistance in TGCTs, starting from the rationale of their ability to induce DNA damage in cells with homologous recombination repair (HRR). Thus far, PARPis have failed to show meaningful clinical activity in platinum-refractory TGCT patients, either alone or in combination with chemotherapy. However, few responses to PARPis in TGCTs have been detected in patients with BRCA1/2, ATM or CHEK2 mutations, reinforcing the idea that patients should be optimally selected for tailored treatments in the era of personalized medicine. Future preclinical and clinical research is needed to further investigate the molecular mechanisms of cisplatin resistance and to identify novel therapeutic strategies in resistant/refractory TGCTs patients.

Keywords: DNA damage response; PARP inhibitors; cisplatin resistance; germ cell tumors; homologous recombination repair; testicular tumors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
Mechanism of Action of Platinum-based Chemotherapy and PARP Inhibitors in DDR. This figure illustrates how platinum-based chemotherapy, such as cisplatin, induces DNA damage by forming intra- and inter-strand cross-links that obstruct DNA replication and transcription, leading to DSBs if left unrepaired. The figure also highlights the role of PARPi, which block the PARP enzyme’s function in repairing DBs.
FIGURE 2
FIGURE 2
PARP inhibitors block the repair of existing DNA damage, leading to an accumulation of single strand DNA breaks (SSBs). When these SSBs occur, PARP is activated and binds to the damaged sites, attempting to facilitate repair. This binding can result in the production of DNA-protein crosslinks. Consequently, replication forks may collapse, resulting in the accumulation of double strand breaks (DSBs). In cells proficient in homologous recombination (HR), these DSBs are effectively repaired through the HR pathway. In contrast, HR-deficient tumor cells lack this repair capability, resulting in unresolved DNA damage that ultimately leads to cell death.
FIGURE 3
FIGURE 3
The figure displays the frequency of mutations in homologous recombination repair (HRR) genes in testicular germ cell tumors (TGCTs). The data, obtained from cBioPortal, includes 11,250 samples from 10,635 patients. This combined study contains samples from three studies: MSK-IMPACT Clinical Sequencing Cohort (MSK, Nat Med 2017), Testicular Germ Cell Tumors (TCGA, PanCancer Atlas), and Testicular Germ Cell Cancer (TCGA, Firehose Legacy).
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