BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition
The development of drug resistance reduces the efficacy of cancer therapy. Tumor cells can acquire resistance to MDM2 inhibitors, which are currently under clinical evaluation. We generated RG7388-resistant neuroblastoma cells, which became more proliferative and metabolically active and were less sensitive to DNA-damaging agents in vitro and in vivo, compared with wild-type cells. The resistance was associated with a mutation of the p53 protein (His193Arg). This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition.
Authors
- Бадлаева Алина Станиславовна (ORCID: https://orcid.org/0000-0001-5223-9767)
- Д. В. Копытова (ORCID: https://orcid.org/0000-0003-1086-6329)
- Sergey V. Pushkarev
- Maria A. Yapryntseva (ORCID: https://orcid.org/0000-0003-2883-7075)
- Nikolay V. Pervushin
- Victoria O. Shipunova (ORCID: https://orcid.org/0000-0001-6361-1042)
- D. K. Nilov (ORCID: https://orcid.org/0000-0002-5067-7939)
- Boris Zhivotovsky (ORCID: https://orcid.org/0000-0002-2238-3482)
- Gelina S. Kopeina (ORCID: https://orcid.org/0000-0002-7143-6923)
Institutions
- Engelhardt Institute of Molecular Biology (RU)
- Lomonosov Moscow State University (RU)
- Karolinska Institutet (SE)
- Institute of Bioorganic Chemistry (RU)
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov of the Ministry of Healthcare of the Russian Federation (RU)
- Moscow State University (TJ)
Publication Details
- Journal
- APOPTOSIS
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1007/s10495-024-02014-8
- Citations
- 3
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.85
Funders
- Cancerfonden
- Karolinska Institutet
- Cancerföreningen i Stockholm
- Lomonosov Moscow State University