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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Xiao, S., Shi, F., Song, H., Cui, J. et al. Cancer Cell. 42 (3): 325-327 (2024).
doi: 10.1016/j.ccell.2024.01.008.
Summary of the findings
Summary of the findingsThe tumor suppressor p53 is the most studied protein (gene) in biology. It is the most frequently mutated protein in cancer, producing thousands of diverse and inactivated mutants. Pharmacological targeting mutant p53 requires a strategy that challengingly restores rather than traditionally inhibits protein function. Over the past decades, approximately 70-100 research groups have reported the identification of small-molecule compounds capable of restoring the tumor-suppressive function to p53 mutants, and 7 of these compounds have entered 23 phase I-III clinical trials covering over 1000 cancer patients.
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In this article, the authors employed 10 widely used p53 assays and evaluated 14 representative generic mutant p53 rescue compounds side-by-side (including all of the 6 commercially available compounds that have entered the clinical trials). Thousands of independent biological samples were generated in the evaluation. However, with the exception of ATO and its analogue PAT, they did not detect any reliable rescue in any of the 10 assays for the evaluated compounds. This result recapitulates the findings in the Cancer Cell paper that first reported rescue of mutant p53 by ATO in 2021.
In this article, the authors employed 10 widely used p53 assays and evaluated 14 representative generic mutant p53 rescue compounds side-by-side (including all of the 6 commercially available compounds that have entered the clinical trials). Thousands of independent biological samples were generated in the evaluation. However, with the exception of ATO and its analogue PAT, they did not detect any reliable rescue in any of the 10 assays for the evaluated compounds. This result recapitulates the findings in the Cancer Cell paper that first reported rescue of mutant p53 by ATO in 2021.
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Future impact
In the field of targeted oncology, the fervor surrounding p53 rescue drugs may be comparable to the fervor surrounding room-temperature superconductors in physics. The surprising findings call for a systematic, head-to-head evaluation of the 70-100 mutant p53 rescue compounds that have been reported, especially those are being trialed in cancer patients.
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