A Personalized Therapeutic Approach for Liver Cancers Expressing the African-Centric P47S Variant of TP53

The P47S missense germline variant of TP53 exists in approximately 2% of Americans of African descent and may account for the increased cancer risk and poorer response to therapy evident in African-descent populations. In this work, we sought to identify personalized therapeutic approaches for cancer containing the P47S variant, with a focus on the most common cancer evident in the P47S mouse, liver cancer. We identify the microtubule-targeting agents lexibulin, colchicine, and combretastatin A-4 as three compounds that bind to the colchicine-binding pocket of the α/β-tubulin dimer, and which show increased efficacy in a P47S liver cancer cell line compared with parental cells with wild-type p53. We find evidence for an unusual mechanism underlying this increased efficacy: Our data indicate that the P47S variant shows increased ability to bind to the peptidyl-prolyl isomerase PIN1; this leads to decreased PIN1-cyclin D1 complexes in P47S cells, along with increased cell-cycle arrest in response to lexibulin.

These findings support the growing literature that particular mutant forms of TP53 may have specific therapeutic vulnerabilities that can be targetable; improved understanding of these unique vulnerabilities can lead to improved understanding of p53 function.