Huang L , Fu L .

	Figure 1. EGFR and its signal pathway. There is subsequent autophosphorylation of the cytoplasmic tyrosine kinase domain, which, with the aid of adapter proteins (e.g., SHC and GRB-2), triggers downstream signaling. The principal pathways included: (1) RAS/RAF/MEK, (2) PI3K/AKT and (3) JAK/STAT pathways.
	Figure 2. Aberration of HER families. Members of HER families get involved in the resistance to EGFR-TKIs. The secondary mutations of EGFR, EGFR-vIII, the overexpression of HER2 or mutations of HER2 contribute to the resistance in the presence of EGFR-TKIs. Compared to the other HER proteins, there are currently no mutational alterations known to confer oncogenic activities to HER3. In most cases, HER3 phosphorylation is driven by one of HER family kinase partners, like HER1 and HER2. What׳s more, resistance can also occur through amplification of the proto-oncogene c-Met and the c-Met-mediated phosphorylation of HER3. HER3 serves as a key activator of downstream PI3K/AKT and MEK/MAPK signal pathways through dimerization with other HER family proteins or other molecules.
	Figure 3. Synchronous activation of redundant kinases and abnormality of the downstream pathway.
	Figure 4. Apoptosis pathway mediated by BIM.
	Figure 5. The potential targets for the relative treatment to overcome the resistance to EGFR-TKIs.

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