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Differential Gene Expression in Erlotinib-Treated Fibroblasts

Wickersham, Karen E.; Hodges, Theresa K.; Edelman, Martin J.; Song, Yang; Nan, Mintong; Dorsey, Susan G.

doi: 10.1097/NNR.0000000000000330
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Background Therapies targeting the epidermal growth factor receptor (EGFR) result in a painful rash, the most common and debilitating toxicity among patients with non-small cell lung cancer (NSCLC) who take EGFR tyrosine kinase inhibitor (TKI) therapy; however, predicting the development and the severity of the rash is difficult.

Objective The aim of this study was to examine how erlotinib—an EGFR TKI that NSCLC patients take to stop or slow tumor growth—altered the transcriptome of dermal fibroblasts.

Methods Dermal fibroblasts (ATCC PCS-201-012) were seeded in cell culture flasks, grown under standard conditions, and transferred to cell culture dishes. Cells were treated once daily for 3 days with erlotinib 100 nM (n = 5), erlotinib 1 μM (n = 5), vehicle 1 μM (dimethyl sulfoxide) (n = 5), or no treatment (n = 5). Total RNA was extracted using a standard TRIzol method and hybridized using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Raw intensities generated from the arrays were normalized using a Robust Multiarray Average method and analyzed using analysis of variance in Limma R software. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis to identify canonical or noncanonical signaling pathways enriched in this dataset.

Results We selected genes for investigation based on their potential role in wound healing (AQP3), rash development (CCL2), fibroblast activation (PALLD), cancer and cancer progression (GDF-15, SLC7A11, MMP12, and DIRAS3), and cell cycle control (CDC6). We were able to validate four of these genes by both Western blot analysis and quantitative polymerase chain reaction (MMP12, CCL2, CDC6, and SLC7A11).

Discussion If found predictive of rash in future studies using patient samples, our findings may help to identify those at risk for severe rash so that (a) the dose of EGFR TKI therapy may be adjusted; (b) additional treatments for the rash can be developed; and/or (c) precise, patient-centered interventions can be developed so that patients with cancer can better self-manage their rash and adhere to EGFR TKI treatment.

Karen E. Wickersham, PhD, RN, was Assistant Professor, School of Nursing, University of Maryland, Baltimore; now Assistant Professor, University of South Carolina, College of Nursing, Columbia, South Carolina.

Theresa K. Hodges, PhD, is Bioinformatics Analyst I, Institute for Genome Sciences, School of Medicine, University of Maryland, Baltimore, Maryland.

Martin J. Edelman, MD, was Director, Medical Thoracic Oncology, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, Maryland; now Professor and Chair, Department of Hematology/Oncology; Deputy Director, Cancer Center for Clinical Research; and G. Morris Dorrance Jr. Chair in Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Yang Song, PhD, is Bioinformatics Analyst II, Institute for Genome Sciences, School of Medicine, University of Maryland, Baltimore, Maryland.

Mintong Nan, BS, was Laboratory Research Technician, Department of Pain and Translational Symptom Science, University of Maryland, Baltimore, School of Nursing, Baltimore, Maryland.

Susan G. Dorsey, PhD, RN, FAAN, is Professor and Chair, Department of Pain and Translational Symptom Science, University of Maryland, Baltimore, School of Nursing, Baltimore, Maryland; and PhD Student at the University of Maryland.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.nursingresearchonline.com).

Accepted for publication September 21, 2018.

Funding was provided by the National Institute of Nursing Research (Genetic, Clinical, and Biological Correlates of EGFR Inhibitor-related Rash, K. E. Wickersham, PI: F32NR014753) and through the University of Maryland, Baltimore, School of Nursing, Center of Biology and Behavior Across the Lifespan (K. E. Wickersham, PI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors thank Dr. Jin Ying, Dr. Yezhou Sun, Bassel Shalaby, and the University of Maryland School of Medicine Center for Innovative Biomedical Resources, Translation Laboratory Shared Services Core (Baltimore, Maryland), for their contributions to this project.

The authors also acknowledge Dr. Alan R. Shuldiner, Professor, University of Maryland, Baltimore, School of Medicine, and Vice President, Regeneron Pharmaceuticals, Inc., and Dr. Claire M. Fraser, Professor and Director, University of Maryland, Baltimore, School of Medicine, Institute for Genome Sciences, for their advice and critical review of this manuscript.

Because no human subjects were enrolled, institutional review board approval was not required.

The authors have no conflicts of interest to disclose.

Corresponding author: Karen E. Wickersham, PhD, RN, University of South Carolina, College of Nursing, 1601 Greene Street, RM 624, Columbia, SC 29208 (e-mail: kwickers@mailbox.sc.edu).

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