The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment
Open accessAbstract
Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities. Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression. Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization. We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/− (R248Q allele) and H/H (R172H allele) mice by 59% and 48%, respectively, but not their corresponding p53−/− littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/− mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target.
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Cites
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
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Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
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Restoration of p53 function leads to tumour regression in vivo
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Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome
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Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling
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Cited by
Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906
Schopf, F. H., Biebl, M. M., & Buchner, J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.20 · Cited by 1,540
Targeting mutant p53 for efficient cancer therapy
Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G. (2018) · Nature Reviews Cancer · doi:10.1038/nrc.2017.109 · Cited by 889
Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others
Sabapathy, K., & Lane, D. P. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.151 · Cited by 517
Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth
Zhu, J., Sammons, M. A., Donahue, G., Dou, Z., Vedadi, M., Getlik, M., Barsyte-Lovejoy, D., Al-awar, R., Katona, B. W., Shilatifard, A., et al. (2015) · Nature · doi:10.1038/nature15251 · Cited by 493
Metadata
- Authors
- Alexandrova, E. M., Yallowitz, A. R., Li, D., Xu, S., Schulz, R., Proia, D. A., Lozano, G., Dobbelstein, M., & Moll, U. M.
- Venue
- Nature
- Published
- 2015-05-25
- Volume
- 523
- Issue
- 7560
- Pages
- 352-356
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1591934633
- Cited by
- 354
- References
- 9
- FWCI
- 16.12
- Type
- journal article
- Language
- en
- Open access
- green
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- Alexandrova, E. M., Yallowitz, A. R., Li, D., Xu, S., Schulz, R., Proia, D. A., Lozano, G., Dobbelstein, M., & Moll, U. M. (2015). Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature. https://doi.org/10.1038/nature14430
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