Target alterations
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DNA damage
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EGFR and its ligands
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EGFR alterations
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Loss of PTPRS |
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EGFR variant III |
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Nuclear translocation |
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SNP EGFR-K521 |
DNA damage response effectors |
EGFR G465R and concurrent EGFR G33S and EGFR N56K |
ERCC1 expression |
Competition with other ligands
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ATR, WEE1 and PARP activation |
Aberrant expression of TGF-a, TGF-b, EGF, HB-EGF, amphiregulin and heregulin |
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EGFR downstream effectors
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STAT3 activation by EGFR, JAK2 or a Src Kinase |
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Src kinase activation |
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RAS/MAPK pathway activation |
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PI3K/Akt/mTOR pathway activation (e.g. PTEN mutation) |
Bypass pathway activation
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Apoptosis evasion
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Survivin expression |
RTK activation
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MET, AXL, HER2, HER3, ROR2, IGF-1R and VEGFR |
Increased XIAP and TRAIL expression |
Apoptosis evasion
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Loss of the tumor suppressor gene TP53
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Metabolism
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Hypoxia (i.e. HIF-1α overexpression) |
Epithelial-to-mesenchymal transition / cancer stem cells
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NEDD4 overexpression |
Expression of lymphotoxin |
miR-139-5p down-regulation |
EGFR methylation |
IL-6/STAT3 pathway activation |
Secretion of CTX-containing extracellular vesicles |
Increased expression of CD44 and Oct-4 |
Upregulation of EMT-related genes |
Upregulation of ABC transporter genes |
Loss of the tumor suppressor gene SMAD4
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Increased ALDH1 expression |
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Epigenetic modifications
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Activation of miR-302 |
Altered expression of growth factor receptors and EMT-related genes by: |
Increased FOXD2-AS1 expression |
DNA methylation |
Up-regulation of histone methyltransferase DOT1L |
Histone modifications |
NEFL promoter hypermethylation |
Chromatin remodeling |
Elevated expression of PAK2 |
Noncoding RNAs |
miR-629-3p expression |
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TME
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Enhanced expression of miR-96-5p |
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ALK1 activation |
T regs and MDSC proliferation |
SDF-1/CXCR4 expression |
T cells exhaustion or impairment |
Cancer associated fibroblasts (CAF) proliferation |
Toll-like receptor 4 (TLR4) pathway activation |
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Cancer associated fibroblasts (CAF) proliferation |