Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Despite the current advances in management, the 5-year survival rate for HNSCC remains around 66%. HPV-negative HNSCC accounts for approximately 70% of all diagnosed HNSCC cases. Therefore, a better understanding of the HPV-negative HNSCC drivers and targetable points may lead to significant clinical advances. NSD2 is a histone methyltransferase that catalyzes histone H3 lysine 36 di-methylation (H3K36me2). Mutations leading to NSD2 loss-of-function are associated with improved outcomes in about 5% of HNSCC, including about 15% of laryngeal carcinoma (LC) patients. In our study, we demonstrate that NSD2 shRNA depletion in JHU-011 and JHU-022 LC cell lines results in a reduction of H3K36me2 levels and reduced cell growth in these cells in vitro. To evaluate downstream cancer signaling regulated by NSD, we performed a reverse-phase protein array (RPPA) upon NSD2 depletion in LC cell lines. Validation of RPPA using Western blot analysis suggests that NSD2 may regulate the expression of critical proteins responsible for the DNA damage response (DDR), including ATM kinase, PTEN, Akt/mTORC1 signaling pathway, and the cell cycle-related protein CDC2/p-CDC2 Y15 (CDK1/p-CDK1 Y15). Taken together, these data identify NSD2 as a likely regulator of the DNA damage response, Akt/mTORC1 signaling, cell cycle transition, and cell growth in HNSCC, suggesting that NSD2 may be a valuable therapeutic target in LC. Citation Format: Ahmed Ismail, Iuliia Topchu, Amr Ismail, Tingting Zhang, Xu Jia, Peter Makhov, Yanis Boumber. NSD2 regulates cell growth and oncogenic signaling pathways in laryngeal carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 592.
Ismail et al. (Fri,) studied this question.