Correlation of an IGF1R RNA activation signature with allostatic load and time to castration resistance in primary prostate cancer patients.

Abstract

e17026 Background: Insulin-like Growth Factor 1 Receptor (IGF1R) functions as a central mediator of nutrient sensing and energy sufficiency through PI3K–AKT signaling, supporting efficient glucose uptake, mitochondrial function, and redox balance. In primary prostate cancer, activation of IGF1R reflects a metabolically stable tumor state. Conversely, low IGF1R signaling may mark early endocrine uncoupling and metabolic stress adaptation, which increases tumor-derived inflammatory signaling and contributes to heightened cumulative physiological stress in the host. This metabolic stress can be measured by allostatic load, as defined by Guidi et al. (PMID: 32799204). We hypothesized that low IGF1R signaling in primary prostate cancer biopsies is indicative of increased allostatic load, and decreased time to castration resistance (CR). Methods: All prostate cancer patients at UIH who had samples of sufficient quality for RNA sequencing between January 2021 and December 2024 were included in the UIH cohort (n = 104). Retrospective chart review was conducted and RNA sequencing was conducted by Tempus Labs. The IGF1R RNA activation signature (IRAS) was developed using RNA-sequencing data from prostate cancer cell line models (CWR-R1, H660, LASCPC-01, LNCaP p53/Rb KO) treated with IGF alone or in combination with IGF1R inhibitor NVP-ADW742. Differentially regulated (fold-change > 1.2) protein-coding genes above minimum expression threshold (TPM > 0.5) were identified, resulting in a 15-gene IRAS signature that was validated using publicly-available patient data sets. IRAS was assessed against allostatic load and patient outcomes in the UIH cohort. Results: In the UIH patient cohort, allostatic load and time to castration-resistance (CR) were calculated between IRAS-high (n = 42) and IRAS-low (n = 62) primary prostate cancer biopsies. IRAS-high biopsies were associated with lower allostatic load vs. IRAS-low ( p = 0.009), suggesting reduced chronic activation of metabolic stress. IRAS-high patients had significantly higher survival probabilities than IRAS-low ( p = 0.044). After controlling for confounding factors (age, race, ethnicity, BMI, Gleason, stage at diagnosis, de novo metastasis, diabetes diagnosis, and A1C), IRAS-low was significantly associated with increased risk of developing CR on androgen deprivation therapy in both univariate ( p = 0.049) and multivariate ( p = 0.042) Cox Proportional Hazard regression modelling. Conclusions: In this study, we demonstrate that an IGF1R RNA activation signature derived from prostate cancer cell line models is clinically informative in primary prostate cancer and captures a biologically meaningful axis linking tumor metabolism, systemic physiological stress, and therapeutic outcomes.