EGFR-TKI resistance in NSCLC patients: mechanisms and strategies

Abstract

The epidermal growth factor receptor (EGFR) is a kind of receptor tyrosine kinase (RTK) that plays a critical role in the initiation and development of malignant tumors via modulating downstream signaling pathways. In non-small cell lung cancer (NSCLC), the activating mutations located in the tyrosine kinase domains of EGFR have been demonstrated in multiple researches as the "Achilles' heel" of this deadly disease since they could be well-targeted by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, it's still too early to celebrate since the first-generation EGFR-TKIs such as gefitinib and erlotinib have only achieved limited clinical benefits and acquired resistance to this kind of drugs occurred inevitably in almost all the NSCLC patients. In order to make the most of EGFR-TKIs and develop more effective regimens for the NSCLC patients, researchers majoring in different aspects start a battle against EGFR-TKI resistance. Challenging as it is, we still progress stably and step firmly toward the final victory. This review will summarize the major mechanisms of acquired resistance to EGFR-TKIs, and then discuss the development of rationally designed molecular target drugs in accordance with each mechanism, in the hope of shedding light on the great achievements we have obtained and tough obstacles we have to overcome in the battle against this deadly disease.

Keywords: Non-small cell lung cancer; drug resistance; epithelial growth factor receptor; molecular targeted therapy; tyrosine kinase inhibitors.

Figure 1

Various mechanisms of EGFR-TKI resistance. Despite of constitutive existence of first-generation of EGFR-TKIs, the tumor cells manage to survive and proliferate via EGFR-T790M mutation, upregulation of MET/HGF, HER2 mutations, overexpression of HER3, persistent activation of IGF-1R, mutations of PIK3CA/AKT, loss or downregulation of PTEN and abnormal dimerization of STAT3.

Figure 2

New agents to overcome EGFR-TKI resistance. To cope with the molecular events responsible for the resistance, multiple targeted agents are developed including the new-generation EGFR-TKIs, MET/HGF inhibitors, HER2 inhibitors, HER3 inhibitors, IGF-1R inhibitors, PIK3CA/AKT inhibitors and STAT3 inhibitors.