Abstract 546: Targeting BRAF mutations in head and neck cancer

Abstract The mitogen-activating protein kinase (MAPK) pathway [RAS/RAF/MEK/MAPK] is a well-known mitogenic pathway essential for regulation of cell proliferation, survival, differentiation, invasion, and apoptosis, etc. In normal cells, upon the binding of external stimuli, activated Ras relays the signals through a RAF-MEK-ERK (MAPKKK-MAPKK-MAPK) phosphorylation cascade, leading to MAPK pathway activation. On the other hand, in cancer cells, aberrations or mutations of the pathway components usually could lead to constitutive activation of the pathway, resulting in dysregulation of these cellular processes. Notably, mutations of MAPK pathway components are found in 18% of head and neck cancer (HNC). Among these, mutations of the serine/threonine-protein kinase B-Raf (BRAF gene) account for about 1.8% of HNC (based on TCGA-HNSCC cohort, USA). Serving as one of the key kinase members of the MAPK pathway, BRAF is considered as a precision drug target in various cancer types, including melanoma, thyroid cancer, and non-small cell lung cancer (NSCLC). While the significance of BRAF mutations remains underexplored in HNC, exceptionally favorable responses to BRAF and MEK inhibition had been reported in HNC patients carrying BRAF-mutations. Based on this, we hypothesize that BRAF mutations may confer drug sensitivity and serve as a predictive biomarker for personalized therapy in HNC. Here, we demonstrated that ectopic overexpression of mutated BRAF resulted in MAPK pathway activation in HNC cell models. We also showed that ectopic BRAFV600E could promote the in vitro growth of head and neck cancer cells in both 2D and 3D culture conditions as well as enhance anoikis resistance, which is a prerequisite for metastasis. Further preliminary results showed that the mutated BRAFV600E mutant could promote the invasiveness of HNC cells. In summary, our findings support that targeting the BRAF mutants could be a potential therapeutic approach or precision treatment for HNC. (This study was supported by the Research Impact Fund (R4015-19F in the period of 6/29/2020-9/7/2021) from the Research Grants Council, University Grants Committee, Hong Kong SAR.) Citation Format: Chun Ho Law, Franky Leung Chan, Vivian Wai Yan Lui. Targeting BRAF mutations in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 546.