PS02.024: PRIMA-1 INDUCES P53-MEDIATED APOPTOSIS BY UPREGULATING NOXA IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA WITH TP53 MISSENSE MUTATION

Background TP53 is associated with the resistance of cytotoxic treatment and patient prognosis, and the mutation rate of TP53 in esophageal squamous cell carcinoma (ESCC) is extraordinarily high, at over 90%. PRIMA-1 (p53 re-activation and induction of massive apoptosis) has recently been reported to restore wild type activity to mutant p53 and induce massive p53-dependent apoptosis. APR-246 (methylated PRIMA-1) has been tested in a phase I/II clinical trial with promising results; however, the effects and mechanism in ESCC remain unknown. This study was designed to assess the antitumor effect of PRIMA-1 treatment in both ESCC cell lines with different TP53 status and an ESCC xenograft model and uncover the molecular mechanism of PRIMA-1. Methods After evaluating the TP53 mutation status of a panel of eleven ESCC cell lines by Sanger sequencing, we assessed the in vitro effect of PRIMA-1 administration on cells with different p53 status by conducting cell viability and apoptosis assays. The expression levels of proteins in TP53-related pathways were examined by Western blotting, while knockdown studies were conducted to investigate the mechanism underlying PRIMA-1’s function. An ESCC xenograft model was further used to evaluate the therapeutic effect of PRIMA-1 in vivo. Results PRIMA-1 markedly inhibited cell growth and induced apoptosis by upregulating Noxa expression in ESCC cell lines with a TP53 missense mutation, whereas no apoptosis was induced in ESCC with wild type TP53 and with TP53 frameshift and nonsense mutations. Importantly, the knockdown of Noxa cancelled the apoptosis induced by PRIMA treatment in ESCC cell lines with a TP53 missense mutation. PRIMA-1 administration, compared with placebo, showed a significant antitumor effect by inducing Noxa in the xenograft model of an ESCC cell line with a TP53 missense mutation. Conclusion PRIMA-1 exhibits a significant antitumor effect, inducing massive apoptosis through the upregulation of Noxa in ESCC with a TP53 missense mutation. Disclosure All authors have declared no conflicts of interest.