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The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring
Beatrice Tosoni1, Eisa Naghshineh2, Irene Zanin1
1Department of Molecular Medicine, University of Padua, Via A. Gabelli, 63, 35121 Padua, Italy.
Abstract:
Well-differentiated/dedifferentiated liposarcomas (WD/DDLPSs) account for ∼60% of all liposarcomas. They have a poor prognosis due to limited therapeutic options. WD/DDLPSs are characterized by aberrant expression of mouse double minute 2 (MDM2), which forms G-quadruplexes (G4s) in its promoter. Here, we investigated the possibility of targeting WD/DDLPSs with small molecules against the MDM2 G4s. Among the molecules tested, the naphthalene diimide derivative QN-302 significantly impaired WD/DDLPS cell growth and its activity strikingly paralleled cell-specific G4 abundance as measured by CUT&Tag and RNA sequencing analysis. QN-302 stabilized MDM2 G4s at the P2 inducible promoter and prevented polymerase progression from the constitutive P1 promoter, thereby inhibiting the formation of full-length MDM2 transcripts. This resulted in the accumulation of p53 through the p53-MDM2 autoregulatory feedback loop, ultimately leading to apoptotic cell death. In patient-derived xenograft mouse models, QN-302 treatment reduced tumour volume distribution and was well tolerated. We have identified a novel and effective therapeutic strategy to reduce MDM2 expression and promote p53 reactivation in tumours harbouring wild-type TP53, such as WD/DDLPSs.
Insights
A new drug, QN-302, targets mouse double minute 2 (MDM2) G-quadruplexes in well-differentiated/dedifferentiated liposarcomas (WD/DDLPSs). This approach reactivates p53, inhibiting tumor growth and promoting cell death.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Well-differentiated/dedifferentiated liposarcomas (WD/DDLPSs) represent a significant portion of liposarcomas, presenting poor prognoses due to limited treatment options.
- Aberrant mouse double minute 2 (MDM2) expression, which forms G-quadruplexes (G4s) in its promoter, is a key characteristic of WD/DDLPSs.
Purpose of the Study:
- To investigate the potential of targeting WD/DDLPSs by developing small molecules that interact with MDM2 G-quadruplexes.
- To evaluate the efficacy of the naphthalene diimide derivative QN-302 against WD/DDLPS cells and in preclinical models.
Main Methods:
- Utilized CUT&Tag and RNA sequencing to measure cell-specific G4 abundance.
- Assessed the impact of QN-302 on WD/DDLPS cell growth, MDM2 G4 stabilization, and polymerase progression.
- Evaluated QN-302 efficacy in patient-derived xenograft mouse models.
Main Results:
- QN-302 significantly inhibited WD/DDLPS cell growth, with activity correlating to G4 abundance.
- QN-302 stabilized MDM2 G4s and prevented full-length MDM2 transcript formation, leading to p53 accumulation and apoptosis.
- In vivo studies showed QN-302 reduced tumor volume and was well-tolerated.
Conclusions:
- QN-302 represents a novel therapeutic strategy for WD/DDLPSs by targeting MDM2 G-quadruplexes.
- This approach effectively reduces MDM2 expression and reactivates p53 in wild-type TP53 tumors.
- The findings support QN-302 as a promising candidate for treating liposarcomas with aberrant MDM2 expression.
