Research Seminar: The p53 mutome: dealing with mutational complexity in cancer therapy

Prof. Dr. Thorsten Stiewe, Institute of Molecular Oncology, Philipps-University Marburg, Germany

Tuesday 9th October, 1.00 p.m., Stacey Lecture Theatre 1

The TP53 gene is arguably the most important tumor suppressor gene and altered in approximately half of all cancer patients. Genetic TP53 alterations are predominantly missense mutations that impair p53’s tumor suppressive activity and, in addition, often endow the mutant p53 protein with novel oncogenic functions that promote tumor progression to a metastatic and drug-resistant state. However, the p53 mutome is complex and mutations are spread across the entire TP53 gene with remarkable functional differences between various mutant p53 proteins. Some mutants clearly gain oncogenic activity – others do not. Likewise, while all p53 mutants are compromised in their tumor suppressor activity, not all are completely dead. In fact, many retain considerable residual tumor suppressive activity. How such varying degrees of mutant p53 activity influence cancer therapy is largely unexplored. I will present examples from mouse cancer models that illustrate how partial loss of p53’s tumor suppressive activity influences therapy responses and discuss gene editing strategies to decipher systematically the functional complexity of the p53 mutome.