The tumor suppressor gene TP53
The p53 protein regulates cellular processes such as cell cycle progression, apoptosis and metabolism through transcriptional transactivation of target genes, for example p21, Puma and Zmat3. The TP53 gene is mutated in around half of all tumors. Most TP53 mutations are missense mutations that disrupt p53's specific DNA binding and transcriptional transactivation activity. A smaller fraction of human tumors carry TP53 nonsense mutations that result in a truncated non-functional p53 protein.
Reactivation of mutant p53: a novel strategy for cancer therapy
The high frequency of TP53-mutations in human tumors makes mutant p53 an interesting target for novel cancer therapy. We identified the compound PRIMA-1 and the structural analog APR-246 (PRIMA-1Met) that induce cell death in TP53 mutant tumor cells and inhibit tumor growth in vivo in mice (Bykov et al. Nature Med. 2002; Bykov et al. Oncogene 2005). PRIMA-1 and APR-246 are converted to the active compound MQ, a Michael acceptor that binds covalently to cysteines in p53's core domain and enhances core domain thermostability (Lambert et al. Cancer Cell 2009; Zhang et al. Cell Death Dis. 2018). We have found that APR-246, via MQ, can perturb cellular redox homeostasis by for example inhibition of thioredoxin reductase and depletion of glutathione (Peng et al. Cell Death Dis. 2013; Mohell et al. Cell Death Dis. 2015; Ceder et al. EMBO Mol. Med. 2021). APR-246 has been tested in several clinical trial sponsored by Aprea Therapeutics (Lehmann et al. J. Clin. Oncol. 2012; reviewed in Tuval et al. Nature Rev. Clin. Oncol. 2024).
We are also developing novel therapy for tumors with TP53 nonsense mutation by pharmacological induction of translational readthrough. We have found that the 5-FU metabolite 5-fluorouridine induces readthrough and expression of fully active full-length p53 in tumor cells carrying R213X nonsense mutant TP53, resulting in apoptotic cell death (Palomar-Siles et al. Cell Death Dis. 2022). We have recently created a new unique knock-in mouse model that carries the Trp53 nonsense mutation R210X (Strandgren et al. Cell Death Dis. 2025). R210X corresponds to R213X, the most common nonsense mutation in human TP53 in cancer. Our model will be an important platform for further development of efficient treatment of tumors with TP53 nonsense mutations.