Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer

Chang Xu, Olga Nikolova, Ryan S. Basom, Ryan M. Mitchell, Reid Shaw, Russell D. Moser, Heuijoon Park, Kay E. Gurley, Michael C. Kao, Carlos L. Green, Franz X. Schaub, Robert L. Diaz, Hallie A. Swan, In S. Jang, Justin Guinney, Vijayakrishna K. Gadi, Adam Margolin, Carla Grandori, Christopher J. Kemp, Eduardo Méndez

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2828-2843
Number of pages16
JournalClinical Cancer Research
Volume24
Issue number12
DOIs
StatePublished - Jun 15 2018

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Precision Medicine
Head and Neck Neoplasms
Small Interfering RNA
Neoplasms
Pharmaceutical Preparations
Therapeutics
Cell Culture Techniques
Genome
Clinical Trials
Genes
Exome
RNA Sequence Analysis
Spindle Apparatus
Comparative Genomic Hybridization
Proteasome Endopeptidase Complex
DNA Sequence Analysis
Keratinocytes
Research Design
Phosphotransferases
Carcinoma, squamous cell of head and neck

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Xu, C., Nikolova, O., Basom, R. S., Mitchell, R. M., Shaw, R., Moser, R. D., ... Méndez, E. (2018). Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer. Clinical Cancer Research, 24(12), 2828-2843. https://doi.org/10.1158/1078-0432.CCR-17-1339

Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer. / Xu, Chang; Nikolova, Olga; Basom, Ryan S.; Mitchell, Ryan M.; Shaw, Reid; Moser, Russell D.; Park, Heuijoon; Gurley, Kay E.; Kao, Michael C.; Green, Carlos L.; Schaub, Franz X.; Diaz, Robert L.; Swan, Hallie A.; Jang, In S.; Guinney, Justin; Gadi, Vijayakrishna K.; Margolin, Adam; Grandori, Carla; Kemp, Christopher J.; Méndez, Eduardo.

In: Clinical Cancer Research, Vol. 24, No. 12, 15.06.2018, p. 2828-2843.

Research output: Contribution to journalArticle

Xu, C, Nikolova, O, Basom, RS, Mitchell, RM, Shaw, R, Moser, RD, Park, H, Gurley, KE, Kao, MC, Green, CL, Schaub, FX, Diaz, RL, Swan, HA, Jang, IS, Guinney, J, Gadi, VK, Margolin, A, Grandori, C, Kemp, CJ & Méndez, E 2018, 'Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer', Clinical Cancer Research, vol. 24, no. 12, pp. 2828-2843. https://doi.org/10.1158/1078-0432.CCR-17-1339
Xu, Chang ; Nikolova, Olga ; Basom, Ryan S. ; Mitchell, Ryan M. ; Shaw, Reid ; Moser, Russell D. ; Park, Heuijoon ; Gurley, Kay E. ; Kao, Michael C. ; Green, Carlos L. ; Schaub, Franz X. ; Diaz, Robert L. ; Swan, Hallie A. ; Jang, In S. ; Guinney, Justin ; Gadi, Vijayakrishna K. ; Margolin, Adam ; Grandori, Carla ; Kemp, Christopher J. ; Méndez, Eduardo. / Functional precision medicine identifies novel druggable targets and therapeutic options in head and neck cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 12. pp. 2828-2843.
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AU - Xu, Chang

AU - Nikolova, Olga

AU - Basom, Ryan S.

AU - Mitchell, Ryan M.

AU - Shaw, Reid

AU - Moser, Russell D.

AU - Park, Heuijoon

AU - Gurley, Kay E.

AU - Kao, Michael C.

AU - Green, Carlos L.

AU - Schaub, Franz X.

AU - Diaz, Robert L.

AU - Swan, Hallie A.

AU - Jang, In S.

AU - Guinney, Justin

AU - Gadi, Vijayakrishna K.

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