Poster Presentation 32nd Lorne Cancer 2020

Identification of novel compounds that induce translational readthrough of nonsense mutant TP53 (#175)

Angelos Heldin 1 , Meiqiongzi Zhang 1 , Mireia Palomar-Siles 1 , Vladimir J.N. Bykov 1 , Klas G Wiman 1
  1. Oncology-Pathology, Karolinska Institutet, Stokholm, Sweden

The tumor suppressor gene TP53 codes for a transcription factor (p53) whose function is to maintain cellular integrity by regulating key processes including DNA repair, cell cycle progression, metabolism, apoptosis and senescence. TP53 is inactivated by mutations in 50% of all human tumors. The majority of TP53 mutations are missense mutations. However, 10% of TP53 mutations are nonsense mutations that lead to expression of a truncated and non-functional p53 protein. An estimated 900 000 cancer patients diagnosed worldwide 2018 have tumors with nonsense TP53 mutation. The most common TP53 nonsense mutation is R213X, which is also the sixth most common TP53 mutation overall. Other common TP53 nonsense mutations are R196X and R342X. There is no available targeted treatment for nonsense mutant TP53-carrying tumors. Therefore, we have performed a high-throughput screening of chemical libraries and performed data mining with the aim of identifying novel compounds that can induce translational readthrough and expression of full-length p53 protein. Our screenings generated more than 80 candidate readthrough inducing compounds (CRICs). We are currently confirming the readthrough-inducing capacity of these compounds by assessing expression of full-length p53 protein in tumor cells carrying R213X nonsense mutant TP53. We will also assess the biological effect of induction of full-length p53 protein in tumors cells. Our goal is to take one or more of the identified compounds to clinical trials in cancer patients with nonsense mutant TP53.