DRUG REPOURPOSING SCREENING STRATEGY TO IDENTIFY MODULATORS OF MUTANT P53 LEVELS IN CANCER CELLS

BORINI, CARLA; SORIA, GASTÓN; LLORENS, MARÍA CANDELARIA; GIRARDINI, JAVIER; GARCIA, AI

Salta

Congreso; SAIB (Sociedad Argentina de Investigación en Bioquímica y Biología Molecular); 2019

SAIB PABMB

Mutation of the TP53 gene is the most frequent genetic alteration found in human cancers. Tumor-associated p53 missense mutants act as drivers of cancer progression, leading to gain-of-function (GOF) phenotypes that promote metastatic potential and drug resistance. Given that mutant p53 protein stabilization is a prerequisite for GOF, the aims of this work was to develop a high-throughput screening assay to identify drugs and molecular pathways that induce destabilization of mutant p53. We setup an In-Cell Western (ICW) assay using an MDA-MB-231 cell line and performed a primary screening with a collection of 1760 FDA-approved drugs. Our preliminary results let to us to identify 34 drugs that induced mutant p53 destabilization, most of them belonging to four major functional groups:1) nucleotide synthesis mediators, 2) agonists and antagonists of steroid hormones, 3) antidepressants and antipsychotics and 4) beta adrenergic agonists. In this work, we will show the design of the screening strategy, the screening results and the early validation of the most robust hits. Our project it focused on the preclinical study of cancer drugs that destabilize mutant p53, using a drug repositioning strategy. Future collaborations can be established for the validation of the best hits.