Data from 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

• DOI: 10.1158/2159-8290.c.7065350.v1
• Publication Date: 2024-02-08T08:43:50Z
• Authors: Zilu Wang; Matteo Burigotto; Sabrina Ghetti; François Vaillant; Tao Tan; Bianca D. Capaldo; Michelle Palmieri; Yumiko Hirokawa; Lin Tai; Daniel S. Simpson; Catherine Chang; Allan Shuai Huang; Elizabeth Lieschke; Sarah T. Diepstraten; Deeksha Kaloni; Chris Riffkin; David C.S. Huang; Connie S.N. Li Wa...; Alexandra L. Garnham; Peter Gibbs; Jane E. Visvader; Oliver M. Sieber; Marco J. Herold; Luca L. Fava; Gemma L. Kelly; Andreas Strasser
• Keywords: Gain of function

<div>Abstract<p>Mutations in the tumor suppressor <i>TP53</i> cause cancer and impart poor chemotherapeutic responses, reportedly through loss-of-function, dominant-negative effects gain-of-function (GOF) activities. The relative contributions of these attributes is unknown. We found that removal 12 different mutants with reported GOFs by CRISPR/Cas9 did not impact proliferation response to chemotherapeutics 15 human cell lines colon cancer–derived organoids culture. Moreover, mutant <i>TP53</i>/<i>TRP53</i> impair growth or metastasis cancers immune-deficient mice murine immune-competent mice. DepMap mining revealed 158 had no on 391 lines. In contrast, CRISPR-mediated restoration wild-type TP53 extinguished cells <i>in vitro</i>. These findings demonstrate LOF but GOF are critical sustain expansion many types.</p>Significance:<p>This study provides evidence <i>TP53</i>, thereby deleting its activities, does survival, proliferation, metastasis, chemotherapy responses cells. Thus, approaches abrogate expression target activities unlikely exert therapeutic cancer.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-1362" target="_blank">See related commentary Lane, p. 211</a></i>.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-14-2-ITI" target="_blank">This article featured Selected Articles from This Issue, 201</a></i></p></div>