Pharmacogenomic landscape of head and neck squamous cell carcinoma informs precision oncology therapy

Abstract

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.

A biomimetic nanoplatform for customized photothermal therapy of HNSCC evaluated on patient-derived xenograft models

“…Primary cell culture of PDC PDC cell culture was performed referred to our previous study. 57 Briefly, specimens were digested in a mixture containing collagenase type IV, liberase, and deoxyribonuclease type I. Consistent with previous reports, a complete F medium was used for further culture.…”

An open, multicenter, exploratory study of apatinib mesylate maintenance therapy for recurrent/metastatic head and neck squamous cell carcinoma (ChiCTR1800019375)

“…Despite the advent of chemotherapeutic therapy, targeted therapy, and immunotherapy in recent decades, less than 50% of patients are cured, and 15%-50% of patients will experience local recurrence or metastasis. 14,15 The prognosis of R/M HNSCC is poor, the treatment effect is not ideal, and the survival time of patients who are resistant to chemotherapy is even shorter. 16,17 It is an urgent clinical problem to improve the survival rate of patients with R/M HNSCC.…”

“…As a heterogenic disease, HNSCC has different prognosis due to different anatomic site, etiology, treatment, and tumor itself. Despite the advent of chemotherapeutic therapy, targeted therapy, and immunotherapy in recent decades, less than 50% of patients are cured, and 15%–50% of patients will experience local recurrence or metastasis 14,15 . The prognosis of R/M HNSCC is poor, the treatment effect is not ideal, and the survival time of patients who are resistant to chemotherapy is even shorter 16,17 .…”

Integrated multiomic analysis and high‐throughput screening reveal potential gene targets and synergetic drug combinations for osteosarcoma therapy

“…Recent advances in phenotypic screening could provide effective compounds for diseases without prior knowledge of treatable targets. 59 For instance, Gu et al 60 conducted a high-throughput drug screen of cells derived from 56 patients with head and neck squamous cell carcinoma (HNSCC) using 2248 compounds. Multiple drugs were identified and could be repurposed for different HNSCC subtypes.…”