摘要
Aberrant activation of the epidermal growth factor receptor(EGFR)is a driving force for cancer growth in a subgroup of non-small cell lung cancer patients.These patients can be identified by the presence of activating EGFR mutations.Currently three generations of EGFR-tyrosine kinase inhibitors(TKIs)have been approved by the Food and Drug Administration and European Medicine Agency.This paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against EGFR-TKIs.These mechanisms include secondary or tertiary mutations in EGFR,the activation of bypassing signaling pathways or a histological transformation to small cell lung cancer.Moreover,drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the brain.Lysosomal sequestration of some EGFR-TKIs may also prevent the drugs to reach their target.In conclusion,resistance to EGFR-TKIs is multifactorial,including primary and acquired mutations in the EGFR gene,activation of bypassing pathways and limited uptake of drugs in the cells or target tissues.More pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.
