Establishment of a chemoresistant laryngeal cancer cell model to study chemoresistance and chemosensitization responses via transcriptomic analysis and a tumor‐on‐a‐chip platform

Tumor resistance to chemotherapy is a common cause of cancer recurrence in patients with head and neck squamous cell carcinoma. The goal of this study is to establish and characterize a chemoresistant laryngeal cancer cell model and test its potential utility for chemosensitizing therapy. At the genotypic level, RNA sequencing confirmed that the cells acquired putative resistance with upregulated docetaxel-resistant (DR) genes (e.g., TUBB3, CYP24A1) and signaling pathways (e.g., PI3K/mTOR, autophagy). For phenotypic analysis, DR cells were co-cultured with laryngeal fibroblasts in a 2-channel microfluidic chip that mimics a hypoxic tumor core in vivo. A drug sensitivity test with a chemosensitizer, metformin (MTF), was performed on the laryngeal tumor-on-a-chip. Compared to non-treated controls, MTF-primed cancer cells exhibit higher sensitivity to docetaxel (DTX), that is, cell death. Collectively, this resistance-acquired cell model displayed presumed genotypic and phenotypic profiles of chemoresistance providing a viable option for testing new therapeutic strategies for restoring tumor sensitivity to DTX.