Potential mechanisms of primary and acquired resistance to anti-EGFR drugs
| Target changes in cancer cells: |
| Somatic EGFR gene mutations leading to resistance to tyrosine kinase inhibitors: T790M |
| Down-regulation of membrane EGFR |
| Nuclear localization of EGFR |
| Activation of downstream signaling pathways through EGFR-independent mechanisms: |
| Increased expression or activation of other cell membrane growth factor receptors: HER2, HER3, MET, IGF1-R, VEGFR-1 |
| Molecular alterations of the PTEN-PI3K-AKT pathway: loss of expression of PTEN, activating mutations of PIK3CA and AKT; |
| Molecular alterations of the RAS-RAF-MEK-ERK pathway: activating mutations of KRAS, NRAS, BRAF. |
| Histologic transformation |
| Epithelial to mesenchymal transition |
| Transformation of non–small cell lung cancer to small cell lung cancer |