Table 1.

Therapeutic strategies and clinical trials to overcome resistance of EGFR-TKIs, "–" stands for no drugs for therapy.

Resistant mechanism	Strategy	Clinical research	Ref.
EGFRmutation
T790M	EGFR-TKIs combined/+antibodies	Afatinib+cexitumab	80
	T790M-specific inhibitors	CO-1686/AZD9291	81, 82
	c-Met inhibitors+PI3K inhibitors	GDC0973+GDC0941	83
	HSP90 inhibitors	Luteolin/ganetespib	11, 84
	EGFR-TKIs+MEK inhibitors	Afatinib+ARQ 197	85
	Glycolysis inhibition+EGFR-TKIs	Afatinib+AUY922	86
Bypass pathway
HER family abnormality	HER inhibitors+EGFR-TKIs	Afatinib/dacomitinib	18, 87
c-Met amplification	EGFR-TKIs+c-Met inhibitors	Erlotinib+crizotinib	88
Dacomitinib+crizotinib
HGF overexpression	EGFR-TKIs+PI3K inhibitors	Gefitinib+PI-103	89
	Triple inhibition of EGFR/Met/VEGF	–	90
IGFR abnormality	IGFR inhibitors+EGFR-TKIs	AG1024+gefitinib	–
EGFRvIII	EGFRvIII antibodies	–	–
VEGF/VEGFR abnormality	EGFR-TKIs+VEGF inhibitors	ZD6474	91
	MEK inhibitors+VEGF inhibitors	ZD6474+PD0325901	30
PDGF/PDGFR abnormality	EGFR-TKIs+PDGF inhibitors	–	–
FGF/FGFR abnormality	EGFR-TKIs+FGF inhibitors	–	–
IL-6 abnormality	IL-6 antibodies	Siltuximab	92
AXL abnormality	AXL inhibitors	NPS-1034	93
CRKL amplification	Unknown	Unknown	–
Integrin beta1 overexpression	Unknown	Unknown	–
Downstream pathway
K-RAS mutations	PI3K inhibitors+MEK inhibitors	GDC-0941+AZD6244	94
BRAF mutations	BRAF inhibitors+MEK inhibitors	Dabrafenib+trametinib	95
Loss of PTEN	mTOR inhibitors/AKT inhibitors	–	–
PIK3CA mutation	EGFR-TKIs+PI3K inhibitors	Gefitinib+BKM120	96
Low expression of NF1	Unknown	Unknown	–
Apoptosis pathway
BIM BH3 deletion	EGFR-TKIs+PP2A activator	Erlotinib+FTY720 gefitinib+FTY720	62
Histologic transformation
EMT	EGFR-TKIs+MEK1/2 inhibitors	–	–
SCLC transformation	Platinum+VP16/EGFR-TKIs	–	–
ABC effusion	EGFR-TKIs+HER-2 inhibitors	GW583340/GW2974	73
Unknown mechanism	EGFR-TKIs combined	Afatinib+cexitumab	80
EGFR-TKIs+glycolysis inhibitors	Erlotinib+AUY922