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 two percent 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 a/b tubulin dimer, and which show increased efficacy in a P47S liver Cancer cell line compared to parental cells with WT 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. IMPLICATIONS: 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.