CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network

Elana J. Fertig, Hiroyuki Ozawa, Manjusha Thakar, Jason D. Howard, Luciane T. Kagohara, Gabriel Krigsfeld, Ruchira S. Ranaweera, Robert M. Hughes, Jimena Perez, Siân Jones, Alexander V. Favorov, Jacob Carey, Genevieve Stein-O'Brien, Daria A. Gaykalova, Michael F. Ochs, Christine H. Chung

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)73845-73864
Number of pages20
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 2016

Fingerprint

Transcription Factor AP-2
Phosphatidylinositol 3-Kinases
Transcriptome
Genes
Neoplasms
Gene Expression
Therapeutics
p16 Genes
erbB-1 Genes
Cell Line
Growth Factor Receptors
Atlases
Mitogen-Activated Protein Kinase Kinases
Computational Biology
Keratinocytes
Oncogenes
Libraries
Inhibition (Psychology)
Genome
Cetuximab

Keywords

  • Cell signaling
  • Crosstalk
  • EGFR
  • Genomics
  • Targeted therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network. / Fertig, Elana J.; Ozawa, Hiroyuki; Thakar, Manjusha; Howard, Jason D.; Kagohara, Luciane T.; Krigsfeld, Gabriel; Ranaweera, Ruchira S.; Hughes, Robert M.; Perez, Jimena; Jones, Siân; Favorov, Alexander V.; Carey, Jacob; Stein-O'Brien, Genevieve; Gaykalova, Daria A.; Ochs, Michael F.; Chung, Christine H.

In: Oncotarget, Vol. 7, No. 45, 2016, p. 73845-73864.

Research output: Contribution to journalArticle

Fertig, EJ, Ozawa, H, Thakar, M, Howard, JD, Kagohara, LT, Krigsfeld, G, Ranaweera, RS, Hughes, RM, Perez, J, Jones, S, Favorov, AV, Carey, J, Stein-O'Brien, G, Gaykalova, DA, Ochs, MF & Chung, CH 2016, 'CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network', Oncotarget, vol. 7, no. 45, pp. 73845-73864. https://doi.org/10.18632/oncotarget.12075
Fertig, Elana J. ; Ozawa, Hiroyuki ; Thakar, Manjusha ; Howard, Jason D. ; Kagohara, Luciane T. ; Krigsfeld, Gabriel ; Ranaweera, Ruchira S. ; Hughes, Robert M. ; Perez, Jimena ; Jones, Siân ; Favorov, Alexander V. ; Carey, Jacob ; Stein-O'Brien, Genevieve ; Gaykalova, Daria A. ; Ochs, Michael F. ; Chung, Christine H. / CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network. In: Oncotarget. 2016 ; Vol. 7, No. 45. pp. 73845-73864.
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AU - Howard, Jason D.

AU - Kagohara, Luciane T.

AU - Krigsfeld, Gabriel

AU - Ranaweera, Ruchira S.

AU - Hughes, Robert M.

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AU - Jones, Siân

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AU - Carey, Jacob

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