The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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4. 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, Z. et al. Cancer Discovery 14(2), 362-379 (2024).
doi: 10.1158/2159-8290.CD-23-0402.
Summary of the findings
The gene that encodes the tumor suppressor TP53 (called Trp53 in the mouse or p53 generically) is the most commonly mutated gene in human cancer. Mutant TP53 proteins have been reported to drive malignant transformation and sustain tumor growth as well as evasion from therapy via loss-of-function (LOF), dominant-negative effects (DNE) and/or gain-of-function (GOF) activities. However, the relative contributions of these three effects to tumorigenesis are controversial. Here, by using a doxycyclin-inducible CRISPR/Cas9 genome editing system, we found that the removal of >10 different TP53 mutants in 15 human cancer cell lines of diverse cellular origin and in patient colon cancer-derived organoids did not impact their survival, proliferation or chemotherapeutic response in culture. Similarly, there was no effect on the growth of human and murine cancer cell lines or the metastasis of murine cancer cell lines in vivo in mice when mutant TP53 was deleted. Our functional data was consistent with previous studies since mining the DepMap database showed no effects on viability of removing 158 different TP53 mutants in almost 400 human cancer cell lines. These results suggest that the GOF effects of mutant TP53 are not essential for the growth, metastasis or therapy evasion of cancers.
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Since our data indicated that the LOF of wild-type (wt) TP53 was contributing to tumor growth, we used CRISPR mediated homology directed repair to convert mutant TP53 to wt TP53 sequence in select human cancer cell lines. The expression of wt TP53 led to rapid death of the tumor cells in vitro. This suggests that drugs that can restore wt functions to mutant TP53 proteins would have therapeutic potential for mutant TP53 cancers.
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Future impact
Our findings across a panel of human cancer cell lines provide important insights into how mutant TP53 contributes to tumorigenesis that inform on therapeutic approaches for mutant TP53 cancers. Our data indicate that it is the LOF of wt TP53 rather than putative GOF effects of mutant TP53 that are permitting tumor growth. We therefore expect that drugs that act to restore wt TP53 functions to mutant TP53 proteins should stop the growth of or kill such cancer cells, thereby exerting substantial therapeutic impact.
4. 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
Summary of the findings
