SELECTIVE DEGRADATION OF ONCOGENIC p53 MUTANTS THROUGH A DRUG REPURPOSING STRATEGY

NABILA COCORDANO; CARLA M. BORINI ETICHETTI; MARÍA CANDELARIA LLORENS DE LOS RÍOS; EVELYN AREL ZALAZAR; GASTÓN SORIA; JAVIER GIRARDINI

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

The presence of missense mutations in the p53 gene is among themost frequent alterations in human cancer. These mutations leadto the expression of mutant p53 proteins, which can actively collaborate with oncogenic processes. Mutant p53 forms have attractedgreat interest as therapeutic targets because their elimination couldreduce the development of aggressive and metastatic tumors. Targeting mutant p53 would also provide highly selective therapies,since mutations are found exclusively in tumor cells, reducing thepossibility of adverse effects. Also, the high mutation frequency ofp53 would make this strategy useful in different cancer types. Intumor cells, p53 point mutants show a remarkable increase in stability compared with the wt protein. In order to identify drugs ableto induce mutant p53 degradation, we performed a high-throughput screening, using libraries of drugs approved for clinical use inhumans against various pathologies. Using In Cell Western Blot,we analyzed the effect of 1760 drugs on the MDA-MB-231 cell line,derived from Triple-Negative breast adenocarcinoma, which endogenously expresses p53R280K mutant. In this way, compoundscapable of significantly reducing mutant p53 levels were identified.We further characterized the effect of a selected candidate. Wedemonstrated that the compound reduced the levels of other p53point mutants in different cell lines (p < 0,001; n=3). Time courseanalysis using western blot showed that the drug decreased thehalf-life of mutant p53 (p < 0,01; n=3), associated with an increasein polyubiquitination. In contrast, wt p53 levels were not affected,suggesting that the effect is selective for cells that express mutantp53. Using wound healing assays we showed that the drug reducedthe migration of cancer cells (p < 0,01; n=3), a characteristic trait ofmetastatic cells promoted by mutant p53. In summary, we identifieda compound potentially useful in antitumor strategies based on mutant p53 degradation.