Table 1.

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