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

LLORENS DE LOS RÍOS, MARÍA CANDELARIA; BORINI, CARLA ; GARCÍA, IRIS ALEJANDRA; GIRARDINI, JAVIER; SORIA, GASTON

Salta

Congreso; XIV Congreso de la Pan-American Association for Biochemistry and Molecular Biology y LV Reunión Anual de la Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular; 2019

Sociedad argentina de investigación en Bioquímica y Biología Molecular

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 aim of this work was to develop a high-throughput screening assay to identify drugs and molecular pathways that induce destabilization of mutant p53. We set up an In-Cell Western (ICW) assay using MDA-MB-231 cells and performed a primary screening with a collection of 1760 FDA-approved drugs. Our preliminary results let us 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 is 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 most promising hits.