Abstract
BackgroundEGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways.MethodsHere we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors.ResultsThe metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis.ConclusionsThis metaanalysis suggests that ‘combination therapies’ can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding development of resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1337-3) contains supplementary material, which is available to authorized users.
Highlights
EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis
For studying EGFR antibody inhibitors responses we found a single study with 3 microarrays from Cetuximab-sensitive and 3 from resistant cell lines, with 48607 genes
In seven datasets EGFR inhibitor-sensitive vs. resistant cell lines were compared without any other treatment
Summary
EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. EGFR dimerizes and triggers Ras-RAF-MEKERK-MAPK, JAK-STAT and other signaling cascades [4,5]. These pathways activate transcription factors, Younis et al BMC Cancer (2015) 15:369 resulting in activation of cellular processes including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth and cell survival [4,6]. EGFR activation is important in maintaining the metabolic homeostasis and stimulates proliferation, invasion, angiogenesis, survival, decreased apoptosis, migration, differentiation and adhesion. Because of its central signaling position, EGFR is targeted in number of malignancies e.g. lung, colorectal, pancreatic, head and neck cancers, glioblastomas etc. [7]
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