EXTH-26. Targeting Amino Acid Transporter in Malignant Peripheral Nerve Sheath Tumors: A Strategy to Enhance Efficacy of Chemotherapy and Targeted Therapy

Abstract OBJECTIVES Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas with limited treatment options and poor prognosis. Similar to other high-grade sarcomas, MPNSTs exhibit elevated metabolic demands and frequently upregulate nutrient transporters to support rapid growth. Our prior work identified overexpression of L-type amino acid transporter 1 (LAT1/SLC7A5) in MPNST, facilitating [¹⁸F]-FDOPA uptake and suggesting its utility as a PET/CT imaging biomarker. JPH203, a selective LAT1 inhibitor, has shown manageable toxicity and tumor-selective activity in early-phase trials for other solid tumors. Given the molecular heterogeneity and frequent treatment resistance in MPNST, we hypothesized that combining LAT1 inhibition with standard therapies could improve therapeutic response. METHODS LAT1 knockdown was achieved via lentiviral shRNA delivery. Antiproliferative effects of LAT1 inhibitors were evaluated in vitro using CCK-8 assays and the IncuCyte® live-cell imaging system. Protein expression of LAT1 and downstream signaling were assessed by SimpleWestern™ (Wes). In vivo efficacy was evaluated in a patient-derived xenograft (PDX) model of MPNST. RESULTS LAT1 inhibitors selectively inhibited proliferation in MPNST cells expressing high levels of LAT1, while LAT1 knockdown abolished this effect, confirming target specificity. JPH203 induced dose-dependent growth inhibition in multiple MPNST cell lines (IC₅₀: 10-30 µM) and reduced phosphorylated p70S6 levels in a dose- and time-dependent manner, indicating mTORC1 pathway suppression. Combination treatment with LAT1 inhibitor and doxorubicin enhanced cytotoxicity compared to monotherapy. Co-treatment of LAT1 inhibitor with MEK inhibitors demonstrated synergistic antiproliferative effects, potentially overcoming resistance driven by PI3K/AKT/mTOR signaling. In vivo evaluation of these combination strategies is ongoing. CONCLUSIONS These findings support LAT1 inhibition as a promising therapeutic strategy in MPNST. Synergy with chemotherapy and targeted agents such as MEK inhibitors highlights the potential to exploit metabolic vulnerabilities and enhance the efficacy of existing treatment regimens in this challenging sarcoma subtype.