Targeting of Deregulated Wnt/β-Catenin Signaling by PRI-724 and LGK974 Inhibitors in Germ Cell Tumor Cell Lines.

Abstract

The majority of patients with testicular germ cell tumors (GCTs) can be cured with cisplatin-based chemotherapy. However, for a subset of patients present with cisplatin-refractory disease, which confers a poor prognosis, the treatment options are limited. Novel therapies are therefore urgently needed to improve outcomes in this challenging patient population. It has previously been shown that Wnt/β-catenin signaling is active in GCTs suggesting that its inhibitors LGK974 and PRI-724 may show promise in the management of cisplatin-refractory GCTs. We herein investigated whether LGK-974 and PRI-724 provide a treatment effect in cisplatin-resistant GCT cell lines. Taking a genoproteomic approach and utilizing xenograft models we found the increased level of β-catenin in 2 of 4 cisplatin-resistant (CisR) cell lines (TCam-2 CisR and NCCIT CisR) and the decreased level of β-catenin and cyclin D1 in cisplatin-resistant NTERA-2 CisR cell line. While the effect of treatment with LGK974 was limited or none, the NTERA-2 CisR exhibited the increased sensitivity to PRI-724 in comparison with parental cell line. Furthermore, the pro-apoptotic effect of PRI-724 was documented in all cell lines. Our data strongly suggests that a Wnt/β-catenin signaling is altered in cisplatin-resistant GCT cell lines and the inhibition with PRI-724 is effective in NTERA-2 CisR cells. Further evaluation of Wnt/β-catenin pathway inhibition in GCTs is therefore warranted.

• Authors: Silvia Schmidtova, Katarina Kalavska, Veronika Liskova, Jana Plava, Svetlana Miklikova, Lucia Kucerova, Miroslava Matuskova, Lucia Rojikova, Zuzana Cierna, Adriana Rogozea, Heiko Konig, Costantine Albany, Michal Mego, Michal Chovanec
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 8 (Apr 20 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33923996 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• ICG 001
• Pyrazines
• Pyridines
• Pyrimidinones
• beta Catenin
• Cisplatin
• LGK974

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, SCID
• Neoplasms, Germ Cell and Embryonal (drug therapy, metabolism)
• Pyrazines (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Pyrimidinones (pharmacology, therapeutic use)
• Testicular Neoplasms (drug therapy, metabolism)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (metabolism)