Functional Precision Medicine Identifies Novel Druggable Targets and Therapeutic Options in Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with high mortality and a lack of targeted therapies. To identify and prioritize druggable targets, we performed genome analysis together with genome-scale siRNA and oncology drug profiling using low-passage tumor cells derived from a patient with treatment-resistant HPV-negative HNSCC. A tumor cell culture was established and subjected to whole-exome sequencing, RNA sequencing, comparative genome hybridization, and high-throughput phenotyping with a siRNA library covering the druggable genome and an oncology drug library. Secondary screens of candidate target genes were performed on the primary tumor cells and two nontumorigenic keratinocyte cell cultures for validation and to assess cancer specificity. siRNA screens of the kinome on two isogenic pairs of p53-mutated HNSCC cell lines were used to determine generalizability. Clinical utility was addressed by performing drug screens on two additional HNSCC cell cultures derived from patients enrolled in a clinical trial. Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices. In contrast, siRNA profiling identified 391 candidate target genes, 35 of which were preferentially lethal to cancer cells, most of which were not genomically altered. Chemotherapies and targeted agents with strong tumor-specific activities corroborated the siRNA profiling results and included drugs that targeted the mitotic spindle, the proteasome, and G-M kinases and We also show the feasibility of drug profiling for patients enrolled in a clinical trial. High-throughput phenotyping with siRNA and drug libraries using patient-derived tumor cells prioritizes mutated driver genes and identifies novel drug targets not revealed by genomic profiling. Functional profiling is a promising adjunct to DNA sequencing for precision oncology. .

Proteomic and Post‐Translational Modification Profiling of Exosome‐Mimetic Nanovesicles Compared to Exosomes

“…The potential value of exosomes as a therapeutic delivery vehicle is increasingly promising, and for many, the safety and feasibility has been demonstrated in clinical trials . However, such utility is hampered by complexity, heterogeneity, spontaneous packaging of cargo, production yield of different cells type, cost, and timeframe in producing sufficient exosomes for downstream application.…”

Expression Patterns of CD44 and AREG Under Treatment With Selective Tyrosine Kinase Inhibitors in HPV+ and HPV− Squamous Cell Carcinoma

“…Together with technological advances, individualized therapeutic options are increasing in response to emerging drug resistance to TKI therapy. In an interesting publication from Xu and colleagues, novel druggable targets in head and neck cancer were identified with high-throughput phenotyping (27). They used different HNSCC cell lines, including UMSCC-14C, and screened target genes for cancer specificity and potential therapeutic drug response, including small-molecule TKIs such as dasatinib.…”

A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin

“…Analyses of patient-derived tumor organoids, for example, could include predictive modeling and experimental validation for development of treatment strategies, both initially and with recurrence [235–237]. The influence of Warburg status could also be integrated into such personalized models if monitoring its influence on responsiveness of cancer to chemotherapy proves useful for selectively killing tumors [238].…”