Mut-p53 acts as a synthetic lethal partner with E2F3 inhibition in gastric cancer under FGFR1 inhibitor.
BACKGROUND Gastric cancer frequently harbors TP53 mutations, posing a challenge for therapies directly targeting mutant p53. Fibroblast growth factor receptor 1 (FGFR1) is a potential therapeutic target, but its interaction with mutant p53 in gastric cancer remains poorly understood. METHODS We evaluated our newly designed FGFR1 inhibitor, S29, across multiple gastric cancer cell lines. Synthetic lethal partners of mutant p53 were identified using the Synthetic Lethality Online Analysis Database and validated through molecular assays, including overexpression and knockdown of p53 and E2F3. Clinical tissue samples were analyzed to confirm the pathological relevance of the FGFR1-E2F3-p53 axis. RESULTS S29 effectively suppressed gastric cancer cell growth while concurrently increasing mutant p53 expression and downregulating E2F3. We identified E2F3 as a synthetic lethal partner of mutant p53. While p53 knockdown abolished S29's inhibitory effects, the combination of mutant p53 accumulation and FGFR1-mediated E2F3 inhibition significantly triggered G2/M cell cycle arrest and programmed cell death. These findings were consistent with expression patterns observed in clinical samples. CONCLUSIONS Our study demonstrates that FGFR1 inhibition induces synthetic lethality in mutant p53 gastric cancer by targeting the E2F3 axis. These results suggest that S29 provides a strategic therapeutic approach for patients with TP53 mutations.