Abstract Background Everolimus (an mTORC1 inhibitor) packaged as Sapu003, an injectable deciparticle formulation, has shown superior cytotoxic activity compared with paclitaxel in glycolysis-addicted tumors. Leveraging retrospective pan-cancer transcriptomic datasets, we explored whether expression of core mTOR-complex scaffolds and metabolic modulators defines a subgroup most likely to benefit from Sapu003 and complementary metabolic therapy. Methods Publicly available survival cohorts (METABRIC, KM-Plotter, TCGA) were mined for overall survival (OS) and relapse-free survival (RFS) according to mRNA quartiles of mTORC1 (RPTOR, AKT1S1) and mTORC2 (RICTOR, MAPKAP1) components plus downstream metabolic genes (SKP2, LDHA, MK, STK11). Differential survival was validated across 9,000 samples spanning breast, lung, gastric, ovarian, RCC and AML. A composite biomarker was derived by recursive partitioning. Results High RICTOR expression—reflecting low baseline mTORC1 activity—was independently associated with prolonged OS (110 months vs 66 months) and RFS (48 vs 31 months) in breast cancer (P = 0.0029 and 4.7 × 10-7, respectively). Low RPTOR amplified OS gains conferred by low-AKT3, low-TSC1 or low-RHEB status in lung adenocarcinoma (median 118-139 vs 57-69 months; P 10-5). Across seven tumour types, simultaneous low expression of ≥3 scaffold genes (RPTOR, MLST8, AKT1S1, MAPKAP1, PRR5L, RICTOR, PRR5, DEPTOR) predicted a ≥1.8-fold improvement in overall survival (OS). In glycolysis-addicted U-87 MG xenografts, Sapu003 achieved durable tumour regression with no weight loss. Conclusions A High RICTOR / Low RPTOR ± metabolic-gene-low signature enriches for tumors with intrinsic dependence on adaptive metabolism and may predict enhanced responsiveness to Sapu003. A Phase I/Ib study will prospectively enroll biomarker-positive patients (high-RICTOR / low-RPTOR breast and non-breast solid tumors) and incorporate pharmacodynamic confirmation of mTORC1 blockade and metabolic rewiring. Citation Format: C. Lee, T. Hoque, S. Qazi, S. saund, C. Hsiao, T. Joh. High RICTOR / Low RPTOR Gene-Expression Signature as a Predictive Biomarker for Intravenous Everolimus Nanoparticle (Sapu003): Rationale for the First-in-Human Trial abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-04-04.
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