Abstract 2422: Genetic aberrations of Anaplastic Lymphoma Kinase (ALK) are functional drivers in head and neck squamous cell carcinoma (HNSCC)

Abstract

Abstract Head and neck squamous carcinoma (HNSCC) is a cancer with high genetic heterogeneity. Fusions of Anaplastic Lymphoma Kinase (ALK) have been widely described as a functional driver for lung cancer. Yet, mutations and amplification of ALK are found in HNSCC as well as many other human cancers. Their biological impacts on cancer cell growth are underexplored. Using the Cancer Genome Atlas (TCGA) HNSCC dataset (Firehose Legacy; N=510), we identified a subset of HNSCC patients harboring ALK aberrations (4%), including 0.4% cases with gene amplification and 3.5% with somatic mutations. Transcriptome analysis showed significant tumor-specific ALK upregulation in 43 adjacent normal-HNSCC tumor pairs (2-fold, p=0.001***, TCGA HNSCC Firehose Legacy). Interestingly, clinical analysis revealed that ~94% HNSCC patients with ALK amplification and mutations have advanced diseases (stage III or IV). Among the HNSCC-associated ALK aberrations, ALK amplification, as well as ALK p.R401L mutations are recurrent events. Thus, we sought to investigate their biological functions by ectopic expressions into an HNSCC cell line, FaDu, via retroviral infection. We found that overexpression of ALK WT gene (mimicking gene amplification) and ALK p.R401L significantly promoted cell proliferation vs. EGFP-control (p=0.0004***, 0.01*, respectively). Clonogenic assay also demonstrated both events to be drivers for colony survival vs. EGFP-control by 120%, 150% (p=0.02*, 0.0025**, respectively). Lastly, both events markedly increase FaDu cells invasiveness by Matrigel invasion assay by 67%, 58% (vs. EGFP-control, p<0.0001****, 0.0001****, respectively). In conclusion, ALK aberrations are functional drivers promoting HNSCC aggressiveness. Acknowledgements: This study is funded by General Research Fund, Research Grant Council, Hong Kong Government, Hong Kong SAR (#17121616 ). VWYL also receives funding supports from General Research Fund, Research Grant Council, Hong Kong Government, Hong Kong SAR (#17121616, #14168517), Research Impact Fund (#R4015-19F, R4017-18), the Health and Medical Research Fund (HMRF#15160691) from the Health and Medical Research Fund, the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region), University-Industry Collaboration Programme (UIM/329; Innovation and Technology Fund, Hong Kong Government, Hong Kong SAR), and the Hong Kong Cancer Fund, Hong Kong SAR. Citation Format: Lan Wang, Thomas Chun Kit Yeung, Hoi-Lam Ngan, Peony Hiu Yan Poon, Vivian Wai Yan Lui. Genetic aberrations of Anaplastic Lymphoma Kinase (ALK) are functional drivers in head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2422.