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TP53 mutations emerge with HDM2 inhibitor SAR405838 treatment in de-differentiated liposarcoma
Abstract
In tumours that harbour wild-type p53, p53 protein function is frequently disabled by the mouse double minute 2 protein (MDM2, or HDM2 in humans). Multiple HDM2 antagonists are currently in clinical development. Preclinical data indicate that TP53 mutations are a possible mechanism of acquired resistance to HDM2 inhibition; however, this resistance mechanism has not been reported in patients. Utilizing liquid biopsies, here we demonstrate that TP53 mutations appear in circulating cell-free DNA obtained from patients with de-differentiated liposarcoma being treated with an inhibitor of the HDM2–p53 interaction (SAR405838). TP53 mutation burden increases over time and correlates with change in tumour size, likely representing selection of TP53 mutant clones resistant to HDM2 inhibition. These results provide the first clinical demonstration of the emergence of TP53 mutations in response to an HDM2 antagonist and have significant implications for the clinical development of this class of molecules.
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“Indeed, an increase in TP53 mutation burden—likely from minor pre‐existing mutant clones—was observed weeks into clinical trials of MDM2 antagonists, correlating with resistance and limited clinical response [113, 114].”
From The TP53 tumor suppressor gene: From molecular biology to clinical investigations (2025) · cites this paper as [114]
In the citing paper
“The safety of SAR405838 alone355 or in combination with MEK inhibitors356 has been established, but the drug activity is limited, and TP53 mutations may occur with long-term administration.357”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [357]
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Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia
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Cited by
Targeting p53 pathways: mechanisms, structures, and advances in therapy
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de Weger, V. A., de Jonge, M., Langenberg, M. H. G., Schellens, J. H. M., Lolkema, M., Varga, A., Demers, B., Thomas, K., Hsu, K., Tuffal, G., et al. (2019) · British Journal of Cancer · doi:10.1038/s41416-018-0355-8 · Cited by 62
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Metadata
- Authors
- Jung, J., Lee, J. S., Dickson, M. A., Schwartz, G. K., Le Cesne, A., Varga, A., Bahleda, R., Wagner, A. J., Choy, E., de Jonge, M. J., Light, M., Rowley, S., Macé, S., & Watters, J.
- Venue
- Nature Communications
- Published
- 2016-08-31
- Volume
- 7
- Issue
- 1
- ISSN
- 2041-1723
- Cited by
- 95
- References
- 5
- Language
- en
- Licence
- creativecommons.org/licenses/by/4.0 (tdm)
- creativecommons.org/licenses/by/4.0 (vor)
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