3402 - Targeting Metabolic Dependencies with Precision Nutrition and Radiotherapy in MYC- and PTEN/AKT-Driven Prostate Cancer

Purpose/Objective(s):

Oncogenic MYC activation and PTEN loss (with consequent AKT hyperactivation) drive distinct metabolic profilesin prostate cancer (PCa), yet how these genotype-linked metabolic states can be therapeutically leveraged to improve cancer outcomesremains unclear. We hypothesized that nutritional interventions imposing defined metabolic constraints would selectively target MYC- versus PTEN/AKT-driven metabolic dependencies and improve radiation response.

Materials/Methods:

Single-cell RNA-seq from human PCa samples (GEO176031) was analyzed with Seurat to identify tumor epithelial cells (NKX3.1+) and compute GSVA pathway scores for fatty acid metabolism, glycolysis, and TCA cycle. Cells were stratified by MYC- and AKT-altered expression. Dependencies were validated in vitro using Myc-CaP (MYC-overexpressing) and Pten-CaP8 (PTEN-loss/AKT-high) cells treated with caloric restriction (CR) ± 6 Gy RT. Metabolic markers (FASN, ACC1, GLUT1, HK2), c-MYC signaling, proliferation (PCNA), and apoptosis (BCL-2) were assessed. In vivo, Myc-CaP flank tumors in FVB mice received ketogenic diet (KD), low-fat diet (LF), or CR ± 10 Gy RT, with tumor growth, survival, and molecular endpoints quantified.

Results:

Single-cell analysis revealed reciprocal metabolic wiring: AKT-high tumors suppressed lipid metabolism programs, whereas MYC-high tumors suppressed glycolysis/TCA programs. In Myc-CaP cells, CR markedly reduced lipogenic markers (FASN ~90%, ACC1 ~20%), and CR+RT further suppressed them (FASN >90%, ACC1 ~80%; p<0.05), while RT alone increased lipid markers. In contrast, glycolytic markers (HK2, GLUT1) were not suppressed and instead increased across groups, consistent with selective lipid vulnerability in MYC-driven cells.

In Pten-CaP8 cells, CR alone had minimal effect on lipid metabolism (p>0.05); however, CR+RT induced broader metabolic collapse, reducing lipid markers (FASN/ACC1/CPT1A ~60–70%; p<0.05) and glycolytic markers (HK2/GLUT1 ~50–60%; p<0.05). Mechanistically, CR reduced c-MYC (~35–40%) with stronger suppression by CR+RT (~70–75%; p<0.05), accompanied by decreased proliferation and anti-apoptotic signaling (PCNA and BCL-2; p<0.05) compared with RT alone.

In vivo, CR+RT achieved robust tumor growth reduction (~80–85% vs RT alone; p<0.05); LF+RT produced a modest reduction (~30%), whereas KD+RT increased tumor growth (~40%). Consistently, CR+RT and LF+RT suppressed lipogenic signaling (ACC1/FASN ~45–60%) and reduced c-MYC/PCNA/BCL-2 (~25–55%; p<0.05) without meaningful suppression of glycolytic markers, supporting MYC-selective lipid targeting.

Conclusion:

Precision nutrition can be genotype-matched to exploit MYC-driven lipid dependency (via CR or LF) or broader AKT-driven vulnerabilities (via CR) for enhanced RT response in PCa. These findings establish a framework for genotype-informed precision nutrition during radiotherapy to improve tumor control by targeting distinct metabolic reprogramming.