A Novel Approach for Cisplatin-Resistant Esophageal Squamous Cell Carcinoma via Amino Acid Transporter LAT1 Inhibition.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) represents an aggressive cancer type associated with poor prognosis, often treated with neoadjuvant chemotherapy (NAC) using cisplatin-based regimens. However, cisplatin resistance limits therapeutic efficacy, necessitating a deeper understanding of resistance mechanisms. L-type amino acid transporter 1 (LAT1) plays a crucial role in amino acid uptake and is linked to cancer cell survival through activation of the mammalian target of rapamycin (mTOR) pathway. The involvement of LAT1 in cisplatin resistance in ESCC remains unclear. METHODS: LAT1 expression in ESCC patient samples post-NAC was evaluated by immunohistochemistry, and its association with clinicopathological factors and survival outcomes was analyzed. ESCC cell lines with varying cisplatin sensitivities were assessed for LAT1 expression using western blotting. Amino acid metabolism was examined via radiotracer uptake of (18)F-FET and (18)F-FDG. RNA sequencing was conducted to identify differentially expressed genes associated with mTOR signaling and autophagy. Finally, the effect of the LAT1 inhibitor JPH203 on cell proliferation was tested. RESULTS: High LAT1 expression was significantly associated with larger tumor size, lymph node metastasis, advanced pathological stage, and poor NAC response. Patients with high LAT1 expression exhibited shorter disease-free survival and overall survival. Cisplatin-resistant ESCC cells (KYSE520) showed elevated LAT1 expression, which further increased following cisplatin treatment. Radiotracer assays revealed that (18)F-FET uptake was significantly higher in KYSE520 after cisplatin treatment compared to the sensitive cell line TE5. RNA sequencing identified regulation of mTOR pathway components and autophagy-related genes in cisplatin-resistant cells. Treatment with JPH203 significantly suppressed cell proliferation, particularly in KYSE520 cells, indicating LAT1's role in sustaining tumor cell survival under chemotherapy stress. CONCLUSION: LAT1 contributes to cisplatin resistance in ESCC by sustaining amino acid metabolism and promoting mTOR-dependent autophagy. Targeting LAT1 with JPH203 enhances cisplatin sensitivity, suggesting that LAT1 inhibition could be a promising therapeutic strategy for overcoming chemoresistance in ESCC.