Pharmacogenomic landscape of head and neck squamous cell carcinoma informs precision oncology therapy.
Chao-Ji ShiYanli YaoGuizhu YangGuo-Pei ZhuZhen TianRui WangQi WuYujue WangYaping WuLan ChenChong WangJiamin GaoXindan KangJie ZhangLizhen WangShengzhong DuanZhong-Ming ZhaoZhiyuan ZhangShuyang SunPublished in: Science translational medicine (2022)
Head and neck squamous cell carcinoma (HNSCC) is a common and frequently lethal cancer with few therapeutic options. In particular, there are few effective targeted therapies. Development of highly effective therapeutic strategies tailored to patients with HNSCC remains a pressing challenge. To address this, we present a pharmacogenomic study to facilitate precision treatments for patients with HNSCC. We established a large collection of 56 HNSCC patient-derived cells (PDCs), which recapitulated the molecular features of the original tumors. Pharmacological assessment of HNSCCs was conducted using a three-tiered high-throughput drug screening using 2248 compounds across these PDC models and an additional 18 immortalized cell lines. We integrated genomic, transcriptomic, and pharmacological analysis to predict biomarkers, gene-drug associations, and validated biomarkers. These results supported drug repurposing for multiple HNSCC subtypes, including the JAK2 inhibitor fedratinib, for low KRT18 -expressing HNSCC cases, and the topoisomerase inhibitor mitoxantrone, for IL6R -activated HNSCC cases. Our results demonstrated concordance between susceptibility predictions from the PDCs and the matched patients' responses to standard clinical medication. Moreover, we identified and experimentally confirmed that high expression of ITGB1 elicited therapeutic resistance to docetaxel and high SOD1 expression conferred resistance to afatinib. We further validated ITGB1 as a predictive biomarker for the efficacy of docetaxel therapy in a phase 2 clinical trial. In summary, our study shows that this HNSCC cell resource, as well as the resulting pharmacogenomic profiles, is effective for biomarker discovery and for guiding precision oncology therapies in HNSCCs.
Keyphrases
- high throughput
- single cell
- clinical trial
- poor prognosis
- palliative care
- end stage renal disease
- newly diagnosed
- adverse drug
- chronic kidney disease
- small molecule
- induced apoptosis
- ejection fraction
- emergency department
- rna seq
- copy number
- bone marrow
- cell cycle arrest
- locally advanced
- cell therapy
- prognostic factors
- randomized controlled trial
- dna methylation
- cell death
- binding protein
- cell proliferation
- transcription factor
- smoking cessation
- double blind
- genome wide
- peritoneal dialysis
- amyotrophic lateral sclerosis
- genome wide identification
- endoplasmic reticulum stress