title: CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network.
abstract: Patients with oncogene driven tumors are treated with targeted therapeutics including EGFR inhibitors. Genomic data from The Cancer Genome Atlas (TCGA) demonstrates molecular alterations to EGFR, MAPK, and PI3K pathways in previously untreated tumors. Therefore, this study uses bioinformatics algorithms to delineate interactions resulting from EGFR inhibitor use in cancer cells with these genetic alterations. We modify the HaCaT keratinocyte cell line model to simulate cancer cells with constitutive activation of EGFR, HRAS, and PI3K in a controlled genetic background. We then measure gene expression after treating modified HaCaT cells with gefitinib, afatinib, and cetuximab. The CoGAPS algorithm distinguishes a gene expression signature associated with the anticipated silencing of the EGFR network. It also infers a feedback signature with EGFR gene expression itself increasing in cells that are responsive to EGFR inhibitors. This feedback signature has increased expression of several growth factor receptors regulated by the AP-2 family of transcription factors. The gene expression signatures for AP-2alpha are further correlated with sensitivity to cetuximab treatment in HNSCC cell lines and changes in EGFR expression in HNSCC tumors with low CDKN2A gene expression. In addition, the AP-2alpha gene expression signatures are also associated with inhibition of MEK, PI3K, and mTOR pathways in the Library of Integrated Network-Based Cellular Signatures (LINCS) data. These results suggest that AP-2 transcription factors are activated as feedback from EGFR network inhibition and may mediate EGFR inhibitor resistance.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Elana J
authors.initials: EJ
authors.lastname: Fertig
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.|Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ozawa
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Manjusha
authors.initials: M
authors.lastname: Thakar
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Howard
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Luciane T
authors.initials: LT
authors.lastname: Kagohara
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Krigsfeld
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.|Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Ruchira S
authors.initials: RS
authors.lastname: Ranaweera
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hughes
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jimena
authors.initials: J
authors.lastname: Perez
authors.affiliation: Personal Genome Diagnostics, Baltimore, MD, USA.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.|Vavilov Institute of General Genetics, Moscow, Russia.|Research Institute for Genetics and Selection of Industrial Microorganisms, Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Favorov
authors.affiliation: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Carey
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.|Lieber Institute for Brain Development, Baltimore, MD, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Stein-O'Brien
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Daria A
authors.initials: DA
authors.lastname: Gaykalova
authors.affiliation: Department of Mathematics and Statistics, The College of New Jersey, Ewing Township, NJ, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Ochs
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.|Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D023281:Genomics / Q000379:methods; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D012984:Software; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D050656:Transcription Factor AP-2; C000614131:CDKN2A protein, human
keywords: EGFR; cell signaling; crosstalk; genomics; targeted therapeutics