Abstract 5390: Metabolic reprogramming and glutamine addiction in squamous cell carcinoma driven by mutant cyclin D1

Abstract Cyclin D1 overexpression contributes to abnormal cell proliferation and tumor development in multiple cancer types. Cyclin D1 overexpression occurs at the highest frequency in head and neck squamous cell carcinoma (HNSCC). Biological events that trigger cyclin D1 overexpression include CCND1 amplification, mutations that impair cyclin D1 degradation, and inactivation of the SCF E3 ubiquitin ligase, Fbxo4 which controls cyclin D1 degradation. We focused on a mutant, cyclin D1T286A, which blocks the nuclear export of cyclin D1 and its subsequent degradation by the 26S proteasome. Cyclin DT286A expression can drive a variety of cancer types murine models including endometrial and mammary carcinoma as well as B-cell lymphoma. However, the molecular mechanisms whereby cyclin DT286A drives cancer progression remain to be fully identified. Here, we demonstrate that cyclin D1T286A drives metabolic reprogramming in squamous cancer cells resulting in glutamine addiction via activation of CDK4/6. Notably, cyclin D1T286A triggers downregulation of IDH3 contributing to cell glutamine dependency to enforce oxidative carboxylation benefiting both generation of biosynthetic intermediates and ATP. A decrease of NAD+/NADH ratio induced by decreased IDH3 results in cellular ATP imbalance and compromised mitochondria which promote cell death under glutamine restriction. Finally, we demonstrate that cyclin D1T286A cooperates with mutant p53 to promote head and neck squamous tumor development in a genetically engineered mouse model. In conclusion, we have uncovered the novel mechanism whereby that cyclin D1T286A drives metabolic reprogramming and HNSCC and our results highlight the potential for targeting glutamine metabolism in cyclin D1-positive HNSCCs. Citation Format: Shuyuan Zhang, Polly Phillips-Mason, J. Alan Diehl. Metabolic reprogramming and glutamine addiction in squamous cell carcinoma driven by mutant cyclin D1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5390.