Secretory carrier membrane protein 3 modulates nuclear ERK1/2 signaling and drug response in triple-negative breast cancer

Introduction Triple-negative breast cancer (TNBC) frequently displays hyperactive mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases 1/2 (ERK1/2) signaling but lacks tractable targets to sustain durable pathway inhibition. Identifying modulators that shape ERK1/2 output and influence responses to ERK1/2 inhibitors is therefore needed. The endosomal trafficking protein secretory carrier membrane protein 3 (SCAMP3) is a positive regulator of epidermal growth factor receptor (EGFR) signaling and ERK1/2-dependent phosphoproteomics programs in TNBC. However, the mechanism by which SCAMP3 modulates ERK1/2 signaling and targeted drug response remains unclear. Methods Here, we combined SCAMP3 knockout with pharmacological ERK1/2 inhibition to evaluate SCAMP3's contributions to MAPK signaling, ERK1/2 distribution, cell-cycle control, apoptosis, and in vivo drug response. Results We found that SCAMP3 expression is upregulated in TNBC models harboring intrinsic MAPK-activating alterations compared with MAPK wild-type breast cancer cells. SCAMP3 knockout reduced RAF-MEK-ERK1/2 signaling, decreased nuclear accumulation of active ERK1/2, arrested the cell cycle, and promoted apoptotic responses. Furthermore, SCAMP3 knockout increased the inhibitory response to the ERK1/2-targeted inhibitor MK-8353 in xenograft models of MAPK wild-type TNBC. Conclusion This study identifies SCAMP3 as an important modulator of ERK1/2 signaling and supports further investigation of SCAMP3 as a potential therapeutic co-target to improve ERK1/2-directed therapies.