Abstract
Purpose: 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.Experimental Design: 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.Results: 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 G2-M kinases WEE1 and CHK1 We also show the feasibility of ex vivo drug profiling for patients enrolled in a clinical trial.Conclusions: 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. Clin Cancer Res; 24(12); 2828-43. ©2018 AACR.
Highlights
Genomic profiling of tumors holds great promise to guide cancer therapy
We identified strategies to capitalize on the tumor’s TP53 mutant status via synthetic lethality with G2/M checkpoint regulators such as WEE1 and CHK1, and vulnerabilities associated with mitotic spindle function, developmental and growth factor pathways, protein degradation machinery, and apoptosis
This study was approved by the institutional review board (IRB) of the University of Washington (UW) and the IRB of the Fred Hutchinson Cancer Research Center (FHCRC)
Summary
Genomic profiling of tumors holds great promise to guide cancer therapy. A central challenge is the difficulty of matching effective drugs to genomic profiles, which are often complex and unique to each patient. Many commonly mutated cancer genes, such as tumor suppressor genes, are difficult to target. A second, no less significant challenge is the shortage of druggable targets and associated therapeutic agents. A recent estimate of the number of genes currently targeted by FDA approved drugs is 109 genes, yet there are ~22,000 genes in the human genome, of which ~10,000 are considered druggable [1]. Even in cases where genome-guided targeted therapy works, development of resistance is common, highlighting the need for new targeted agents or combination therapies
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