circSCAP-encoded SCAP-129aa mediates platinum resistance in triple-negative breast cancer via the PI3K/AKT pathway

Triple-negative breast cancer (TNBC) often acquires resistance to platinum-based chemotherapy, presenting significant challenges to therapeutic management and adversely affecting patient survival. In such refractory cases, even advanced treatment modalities often exhibit diminished efficacy. This study aims to elucidate the molecular mechanisms underlying platinum resistance. Circular RNA circSCAP was found to be markedly upregulated in platinum-resistant TNBC and shown to encode a peptide, SCAP-129aa, which is likewise elevated in resistant tumors. Functional analyses revealed that silencing circSCAP in resistant tumors restores sensitivity to platinum-based chemotherapy, whereas its overexpression in sensitive tumors induces resistance. Mechanistically, SCAP-129aa directly interacts with the SH2C domain of PIK3R2, inhibiting its ubiquitination and subsequent degradation. This interaction stabilizes PIK3R2 protein and activates the PI3K/AKT signaling pathway, a key mediator of chemoresistance. Notably, in vivo studies further indicated that either silencing circSCAP or co-administering the PIK3R2 inhibitor SAR-260301 with platinum significantly improves treatment efficacy in resistant TNBC models. These findings establish circSCAP and SCAP-129aa as promising biomarkers and potential therapeutic targets for overcoming platinum resistance in TNBC.