Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and although new therapeutic approaches have been recently evaluated, overall patient survival is still poor. Thus, new effective and selective clinical treatments are urgently needed. An analysis of data from large-scale, high-throughput drug screening cell line projects identified Bosutinib, a Src/Abl inhibitor that is currently used for the treatment of chronic myelogenous leukemia, as a candidate drug to treat HNSCC. Using a panel of HNSCC-derived cell lines, we found that treatment with Bosutinib reduced cell proliferation and induced apoptosis of sensitive cell lines. The drug rapidly inhibited Src and EGFR (epidermal growth factor receptor) phosphorylation, and sensitivity to Bosutinib was correlated with the activation status of EGFR. Similar findings were observed in in vivo xenograft assays using HNSCC derived cells. Moreover, in the presence of mutations in PIK3CA, the combination of Bosutinib with the PI3Kα inhibitor Alpelisib showed a synergistic effect. These results suggest that Bosutinib could be a new effective drug for the treatment of HNSCC, particularly in tumors with high EGFR activity. Its combination with Alpelisib could especially benefit patients bearing activating mutations of PIK3CA.
Highlights
Head and neck cancer arises in the oral and nasal cavities, pharynx and larynx, and in more than 90% of cases, is of squamous origin
Due to the increasing understanding of the molecular mechanisms and basic pathways in the pathogenesis of Head and neck squamous cell carcinoma (HNSCC), current research is focused on molecularly-targeted therapies specific for the pathways involved in the carcinogenesis of HNSCC, such as the epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) pathways
We found that sensitivity to Bosutinib in HNSCC cell lines is dependent on increased EGFR activity
Summary
Head and neck cancer arises in the oral and nasal cavities, pharynx and larynx, and in more than 90% of cases, is of squamous origin. Cetuximab, a monoclonal, anti-EGFR antibody that binds to EGFR and prevents activation of the downstream signaling pathway, was, until recently, the only approved targeted agent for HNSCC therapy. This medicine can inhibit cell growth and survival and has demonstrated overall survival improvements in clinical trials when combined with radiotherapy or chemotherapy [6,7]. New drugs targeting the pathway in a different way as well as co-targeting strategies are under investigation Another cell-growth pathway altered in HNSCC is the PI3K/Akt/mTOR, with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α) being the most commonly altered gene. Activating mutations in PIK3CA have been found in ~20% of HNSCC cases with hot-spot E543K, E545K and H1047R substitutions being the most common [4,9,10]
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