Table 2. Known mechanisms of either primary or acquired resistance to gefitinib or erlotinib in advanced NSCLC patients with activating EGFR gene mutations.

Mechanisms of resistance
Primary	Acquired
Exon 20 insertions (42,43)	Secondary T790M mutation (44-47)
T790M mutation (48,49)	Non-T790M secondary EGFR mutation (46,50,51)
HGF overexpression (52)	MET gene amplification (47,53)
	PI3KCA mutation (54)
	Histologic change from NSCLC to SCLC (54)
	HGF overexpression (52,55)
	IGF-1R hyperphosphorylation (56)

EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor; IGF-1R, nsulin-like growth factor-1; NSCLC, non-small cell lung cancer; PI3KCA, phosphatydil inositol 3-kinase catalytic subunit; SCLC, small cell lung cancer.