Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model
Open accessAbstract
Significance: Emergence of resistance to targeted therapy constitutes a limitation to long-term clinical benefits in many instances. To anticipate potential mechanisms of resistance to double minute 2 protein (MDM2) inhibitors, we performed a piggyBac insertional mutagenesis screen in a cohort of allografts with an underlying CDKN2A deletion, in the presence and absence of the MDM2 inhibitor HDM201. Among the most frequent events conferring resistance, we found several mechanisms converging on direct or indirect loss-of-function inactivation of tumor protein 53 (TP53), as well as activation of the antiapoptotic B-cell lymphoma-extra large ( Bcl-xL ) gene. Importantly, our findings were confirmed in patient-derived xenograft models, underlining the benefit of large-scale in vivo forward genetic screening to identify potential resistance mechanisms to targeted therapeutics.
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NVP-HDM201 prevents p53 degradation by interfering with the interaction between human and mouse MDM2-p53, and has good pharmacokinetic and pharmacodynamic characteristics in animals, as well as good oral bioavailability.
“It prevents p53 degradation by interfering with the interaction between human and mouse MDM2-p53, and has good pharmacokinetic and pharmacodynamic characteristics in animals, as well as good oral bioavailability.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [393]
In preclinical studies, both once daily and once every three weeks dosing regimens of NVP-HDM201 showed comparable long-term efficacy.
“In preclinical studies, both once daily and once every three weeks dosing regimens showed comparable long-term efficacy.393,394”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [393]
NVP-HDM201 (siremadlin) is an imidazolpyrrolidone analog developed by Novartis that has demonstrated highly favorable in vivo properties as an orally effective and selective MDM2-p53 inhibitor.
“NVP-HDM201 (147), also known as siremadlin, is an imidazolpyrrolidone analog developed by Novartis that has demonstrated highly favorable in vivo properties as an orally effective and selective MDM2-p53 inhibitor and recently entered phase I clinical trials in cancer patients.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [393]
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- Authors
- Chapeau, E. A., Gembarska, A., Durand, E. Y., Mandon, E., Estadieu, C., Romanet, V., Wiesmann, M., Tiedt, R., Lehar, J., de Weck, A., Rad, R., Barys, L., Jeay, S., Ferretti, S., Kauffmann, A., Sutter, E., Grevot, A., Moulin, P., Murakami, M., Sellers, W. R., Hofmann, F., & Jensen, M. R.
- Affiliations
- Novartis Institutes for BioMedical Research (CH)
- Novartis (Switzerland) (CH)
- Oncology Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA 02139;
- Oncology Disease Area, Novartis Institutes for BioMedical Research, 4056 Basel, Switzerland;
- German Cancer Research Center (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-03-06
- Volume
- 114
- Issue
- 12
- Pages
- 3151-3156
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5373361
- OpenAlex
- W2593682768
- Cited by
- 64
- References
- 59
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 6 · 2023: 10 · 2022: 4 · 2021: 10 · 2020: 5 · 2019: 8 · 2018: 7 · 2017: 1
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Novartis (no grant)
- German Research Council (SFB1243)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- drug resistance mechanisms, MDM2 inhibitors, forward genetic screen, CDKN2A deletion, p53 inactivation, anti-apoptotic signaling, patient-derived xenografts, targeted therapy
- MeSH terms
- Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Disease Models, Animal, DNA Transposable Elements, Genetic Vectors, Humans, Neoplasms, Biomarkers, Tumor, Tumor Suppressor Protein p53, Mutagenesis, Insertional, Mice, Knockout, Drug Resistance, Neoplasm, Genetic Drift, bcl-X Protein, Mice, Proto-Oncogene Proteins c-mdm2, Kaplan-Meier Estimate, Allografts
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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