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Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells

Wang, Zilu, Burigotto, Matteo, Ghetti, Sabrina, Vaillant, François, Tan, Tao, Capaldo, Bianca D., Palmieri, Michelle, Hirokawa, Yumiko, Tai, Lin, Simpson, Daniel S., Chang, Catherine, Huang, Allan Shuai, Lieschke, Elizabeth, Diepstraten, Sarah T., Kaloni, Deeksha, Riffkin, Chris, Huang, David C.S., Li Wai Suen, Connie S.N., Garnham, Alexandra L., Gibbs, Peter, Visvader, Jane E., Sieber, Oliver M., Herold, Marco J., Fava, Luca L., Kelly, Gemma L., Strasser, Andreas·2024·Cancer Discovery
DOI 10.1158/2159-8290.cd-23-0402

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Abstract

Mutations in the tumor suppressor TP53 cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects and gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal of 12 different TP53 mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation and response to chemotherapeutics of 15 human cancer cell lines and colon cancer–derived organoids in culture. Moreover, removal of mutant TP53/TRP53 did not impair growth or metastasis of human cancers in immune-deficient mice or growth of murine cancers in immune-competent mice. DepMap mining revealed that removal of 158 different TP53 mutants had no impact on the growth of 391 human cancer cell lines. In contrast, CRISPR-mediated restoration of wild-type TP53 extinguished the growth of human cancer cells in vitro. These findings demonstrate that LOF but not GOF effects of mutant TP53/TRP53 are critical to sustain expansion of many tumor types. Significance: This study provides evidence that removal of mutant TP53, thereby deleting its reported GOF activities, does not impact the survival, proliferation, metastasis, or chemotherapy responses of cancer cells. Thus, approaches that abrogate expression of mutant TP53 or target its reported GOF activities are unlikely to exert therapeutic impact in cancer. See related commentary by Lane, p. 211 . This article is featured in Selected Articles from This Issue, p. 201

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Metadata

Authors
Wang, Z., Burigotto, M., Ghetti, S., Vaillant, F., Tan, T., Capaldo, B. D., Palmieri, M., Hirokawa, Y., Tai, L., Simpson, D. S., Chang, C., Huang, A. S., Lieschke, E., Diepstraten, S. T., Kaloni, D., Riffkin, C., Huang, D. C. S., Li Wai Suen, C. S. N., Garnham, A. L., Gibbs, P., Visvader, J. E., Sieber, O. M., Herold, M. J., Fava, L. L., Kelly, G. L., & Strasser, A.
Affiliations
  • 1The Walter and Eliza Hall Institute (WEHI), Melbourne, Australia.
  • 3Armenise-Harvard Laboratory of Cell Division, Department of Cellular, Computational and Integrative Biology – CIBIO, University of Trento, Trento, Italy.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2023-10-24
Volume
14
Issue
2
Pages
362-379
ISSN
  • 2159-8274
  • 2159-8290
DOI
10.1158/2159-8290.cd-23-0402
Cited by
111
References
9
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 107 d)
Funders
  • Cancer Council Victoria (1086157, 1147328)
  • National Health and Medical Research Council (1086291, 2002618, 2001201, 101671, 1020363, 1102742, 1136119)
  • Fondazione AIRC per la ricerca sul cancro ETS (23560)
  • Giovanni Armenise-Harvard Foundation (CDA 2017)
  • Leukaemia Foundation (no number)
  • Leukemia and Lymphoma Society (7001-13)
  • Victorian Cancer Agency (MCRF 17028)

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CoChat. (2026). Citation check: Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells. https://app.cochat.ai/papers/10.1158/2159-8290.cd-23-0402
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Wang, Z., Burigotto, M., Ghetti, S., Vaillant, F., Tan, T., Capaldo, B. D., Palmieri, M., Hirokawa, Y., Tai, L., Simpson, D. S., Chang, C., Huang, A. S., Lieschke, E., Diepstraten, S. T., Kaloni, D., Riffkin, C., Huang, D. C. S., Li Wai Suen, C. S. N., Garnham, A. L., . . . Strasser, A. (2024). Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-23-0402

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