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The MDM2 Inhibitor Navtemadlin Arrests Mouse Melanoma Growth In Vivo and Potentiates Radiotherapy

Ingelshed, Katrine (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Spiegelberg, Diana, 1982- (författare)
Uppsala universitet,Öron-, näs- och halssjukdomar,Cancerprecisionsmedicin
Kannan, Pavitra (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
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Påvénius, Linnéa (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Hacheney, Jessica (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Jiang, Long (författare)
Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden
Eisinger, Silke (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Lianoudaki, Danai (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Lama, Dilraj (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Castillo, Francisca (författare)
Center for Molecular Medicine, Stockholm, Sweden; Division of Immunology and Allergy, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
Bosdotter, Cecilia (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Kretzschmar, Warren W. (författare)
Vanadis Diagnostics, PerkinElmer Inc, Sollentuna, Sweden
Al-Radi, Omayma (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Fritz, Nicolas (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Villablanca, Eduardo J. (författare)
Center for Molecular Medicine, Stockholm, Sweden; Division of Immunology and Allergy, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
Karlsson, Mikael C. I. (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
Wermeling, Fredrik (författare)
Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Stockholm, Sweden
Nestor, Marika, 1976- (författare)
Uppsala universitet,Cancerprecisionsmedicin
Lane, David P. (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Sedimbi, Saikiran K. (författare)
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
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Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Öron-, näs- och halssjukdomar (creator_code:org_t)
2022-09-28
2022
Engelska.
Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 2:9, s. 1075-1088
Relaterad länk:
https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • The tumor suppressor protein p53 is mutated in close to 50% of human tumors and is dysregulated in many others, for instance by silencing or loss of p14ARF. Under steady-state conditions, the two E3 ligases MDM2/MDM4 interact with and inhibit the transcriptional activity of p53. Inhibition of p53–MDM2/4 interaction to reactivate p53 in tumors with wild-type (WT) p53 has therefore been considered a therapeutic strategy. Moreover, studies indicate that p53 reactivation may synergize with radiation and increase tumor immunogenicity. In vivo studies of most MDM2 inhibitors have utilized immunodeficient xenograft mouse models, preventing detailed studies of action of these molecules on the immune response. The mouse melanoma cell line B16-F10 carries functional, WT p53 but does not express the MDM2 regulator p19ARF. In this study, we tested a p53-MDM2 protein–protein interaction inhibitor, the small molecule Navtemadlin, which is currently being tested in phase II clinical trials. Using mass spectrometry–based proteomics and imaging flow cytometry, we identified specific protein expression patterns following Navtemadlin treatment of B16-F10 melanoma cells compared with their p53 CRISPR-inactivated control cells. In vitro, Navtemadlin induced a significant, p53-dependent, growth arrest but little apoptosis in B16-F10 cells. When combined with radiotherapy, Navtemadlin showed synergistic effects and increased apoptosis. In vivo, Navtemadlin treatment significantly reduced the growth of B16-F10 melanoma cells implanted in C57Bl/6 mice. Our data highlight the utility of a syngeneic B16-F10 p53+/+ mouse melanoma model for assessing existing and novel p53-MDM2/MDM4 inhibitors and in identifying new combination therapies that can efficiently eliminate tumors in vivo.Significance:The MDM2 inhibitor Navtemadlin arrests mouse tumor growth and potentiates radiotherapy. Our results support a threshold model for apoptosis induction that requires a high, prolonged p53 signaling for cancer cells to become apoptotic.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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Molekylär medicin
Molecular Medicine

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