Heterogeneity of TP53 mutations necessitates differentiation with p53-rescue therapies

Abstract

We read with interest the Review by Peuget et al. (Peuget, S., Zhou, X. & Selivanova, G. Translating p53-based therapies for cancer into the clinic. Nat. Rev. Cancer 24, 192–215 (2024))¹ that introduces the development of p53-based therapies. We fully agree with the tremendous clinical value of p53-targeting drugs, as TP53 is the most commonly mutated gene in cancer¹. However, we would like to point out that the descriptions of small-molecule compounds that can rescue two or more different types of p53 mutant need to be given with extreme caution. Of the 23 registered p53-rescue trials, 17 trials are investigating these compounds in over 1,000 patients with cancer without differentiating the TP53 mutations (Supplementary Table 1).

Small-molecule compounds that bind mutant p53 and restore its tumour-suppressive function have been extensively pursued over the past decades, with at least 71 rescue compounds identified^2,3,4. The majority of these are termed generic rescue compounds and can rescue numerous mutants simultaneously, spawning hundreds of basic and clinical studies using these compounds to rescue arbitrarily selected p53 mutants. However, based on the logic derived from the diverse mechanisms of action of p53 mutants (Fig. 1b) and increasing experimental validations^5,6,7, a consensus is forming that no generic rescue compound can provide a ‘one-size-fits-all’ solution to rescue two or more types of p53 mutant. For example, a p53-thermostabilizing compound can shift the ‘unfolding–folding’ dynamic balance towards folding, thereby promoting the refolding of structural mutants and rescuing them. Thus, such a compound is both mechanistically and experimentally validated as ineffective in rescuing p53 truncation mutants that lack large stretches of amino acids, or DNA-contact mutants that lack DNA-binding amino acids^5,6,7. Similarly, a DNA-contact mutant-rescue compound (if one were to exist) should act by compensating for the lost DNA-binding amino acids and, thus, mechanistically could not rescue structural mutants, which are unfolded.