Abstract LB047: Pdcd10 is a promising therapeutic target for head and neck squamous cell carcinoma

Abstract Oral cavity squamous cell carcinoma (OCSCC), the most common subtype of head and neck cancer, is a devastating disease, causing substantial morbidity and mortality. Only a handful of targeted therapies are available for OCSCC, and the 5-year overall survival remains ~50%. While strategies are being designed to improve risk assessment, detection, and therapeutic intervention, these approaches are limited by our incomplete understanding of OCSCC biology, particularly in its early development. Thus, it is crucial to identify novel targets of therapeutic interest. Programmed cell death 10 (PDCD10) is a multifaceted protein shown to be overexpressed in several solid malignancies. It was reported that PDCD10 may contribute to tumorigenesis and chemoresistance by promoting cell proliferation, anti-apoptosis, epithelial-mesenchymal transition (EMT), and inhibiting anti-tumor immune responses. Recently it was suggested that PDCD10 is involved in regulating cancer stem cells (CSCs) maintenance in breast and lung cancers. While targeting PDCD10 activity may provide novel strategies for treating HPV- HNSCC, the direct relevance of PDCD10 in regulating head and neck tumorigenesis has not yet been studied. The goal of this study was to evaluate the role of PDCD10 in driving oral malignant transformation and investigate whether PDCD10 inhibition can induce anti-cancer effect. We first generated stable PDCD10 knockdown clones using two human OCSCC cell lines and showed that PDCD10 depletion effects oral cancer cell physiology (such as proliferation, DNA replication, migration, and invasion). We next used organoid models established from normal oral epidermis of tamoxifen inducible Pdcd10F/F and control Pdcd10+/+ mice to investigate the role of PDCD10 in driving oral tumorigenesis and regulating stem cell maintenance following malignant transformation induced by 4NQO treatment. Finally, we used mice with inducible Pdcd10 knockout in tongue epithelia to evaluate the ability of PDCD10 depletion to inhibit the 4NQO induced oral carcinogenesis in vivo. Taken together, our data provide strong evidence that PDCD10 is an oncogene that may promote oral neoplastic progression, posing PDCD10 as a potential therapeutic target for patients with OCSCC. Given the devastating nature of oral cancer and dearth of effective treatment, providing new insights into the cancer driving molecular mechanisms regulated by PDCD10 and using this knowledge for developing therapeutic approaches targeting its activity may ultimately improve patients' prognosis. Citation Format: Manu Sundaresan, Xiangying Cheng, Claudia WIng, Alexander von Kumberg, Elena Jochum, Alka Singh, Joseph Kainov, Piao Zhao, Mohammed Sidahmed, Alexander T. Pearson, Ari J. Rosenberg, Nishant Agrawal, Le Shen, Evgeny Izumchenko. Pdcd10 is a promising therapeutic target for head and neck squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB047.