Potential New Therapeutic Approaches for Cisplatin-Resistant Testicular Germ Cell Tumors

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Lengert, Andre van Helvoort ; Braga Pereira, Leticia do Nascimento ; Martins Cabral, Eduardo Ramos ; Faria Gomes, Izabela Natalia ; de Jesus, Lais Machado ; Santiago Goncalves, Maria Fernanda ; da Rocha, Aline Oliveira ; Tassinari, Tiago Alexandre ; da Silva, Luciane Sussuchi ; Laus, Ana Carolina ; Vidal, Daniel Onofre ; Pinto, Mariana Tomazini ; Reis, Rui Manuel ; Lopes, Luiz Fernando

• Document type: Journal article
• Source: FRONTIERS IN BIOSCIENCE-LANDMARK; v. 27, n. 8, p. 13-pg., 2022-08-15.

Abstract

Background: Testicular germ cell tumors (TGCTs), a group of heterogeneous neoplasms, are the most frequent tumors of teenagers and young men, with the incidence rising worldwide. High cure rates can be achieved through cisplatin (CDDP)-based treatment, but approximately 10% of patients present refractory disease and virtually no treatment alternatives. Here, we explored new strategies to treat CDDP-resistant. Methods: In vitro TGCT CDDP-resistance model was established and differential mRNA expression profiles were evaluated using NanoString technology. Then, TGCT cell lines were treated with four potential drugs (PCNA-I1, ML323, T2AA, and MG-132) to overcome CDDP-resistance. Results: We found several differentially expressed genes related to DNA repair and cell cycle regulation on CDDP-resistant cell line (NTERA-2R) compared to parental cell line (NTERA-2P), and the proteasome inhibitor MG-132 demonstrated cytotoxic activity in all cell lines evaluated, even at a nanomolar range. MG-132 also enhanced cell lines' sensitivity to CDDP, increasing apoptosis in both NTERA-2P and NTERA-2R. Conclusions: MG-132 emerges as a potential new drug to treat CDDP-resistant TGCT. Targeted therapy based on molecular mechanism insights may contribute to overcome acquired chemotherapy CDDP-resistance. (AU)

• FAPESP's process: 17/22305-9 - Study of biomarkers of cetuximab response and perspective of application of anti-EGFR combi-molecules in solid tumors
• Grantee: Izabela Natalia Faria Gomes
• Support Opportunities: Scholarships in Brazil - Doctorate