Abstract
Epidermal growth factor receptor (EGFR) T790M mutation is the most frequent mechanism which accounts for about 60% of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations. Irreversible EGFR-TKIs which include the second-generation and third-generation EGFR-TKIs are developed to overcome T790M mediated resistance. The second-generation EGFR-TKIs inhibit the wide type (WT) EGFR combined with dose-limiting toxicity which limits its application in clinics, while the development of third-generation EGFR-TKIs brings inspiring efficacy either in vitro or in vivo. The acquired resistance, however, will also occur and limit their response. Understanding the mechanisms of resistance to irreversible EGFR-TKIs plays an important role in the choice of subsequent treatment. In this review, we show the currently known mechanisms of resistance which can be summarized as EGFR dependent and independent mechanisms and potential therapeutic strategies to irreversible EGFR-TKIs.
Highlights
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) significantly improve the outcomes as an initial treatment in non-small cell lung cancer (NSCLC) patients with activating Epidermal growth factor receptor (EGFR) mutations compared with standard platinum-doublet chemotherapy
Epidermal growth factor receptor (EGFR) T790M mutation is the most frequent mechanism which accounts for about 60% of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients harboring EGFR activating mutations
T790M mutation was confirmed to be the resistance mechanism of second-generation EGFR-TKIs in tissue specimen. It is still the most important mechanism accounting for 30–50% of the resistance both in reversible EGFR-TKIs naive patients and treated patients according to the rencent studies. [18, 19]. (Table 2) But the phase II B lux-lung 7 (NCT01466660) study indicated that afatinib significantly prolonged the progression-free survival (PFS)
Summary
The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) significantly improve the outcomes as an initial treatment in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations compared with standard platinum-doublet chemotherapy. In cell lines with EGFR T790M mutation, the more resistant subclones harboring amplified T790M in cis with EGFR activating mutation would be selected leading to a more robust resistance under the treatment of high dose of dacomitinib [16, 17]. These pre-clinical studies indicate that the second-generation EGFR-TKIs cannot prevent the occurrence of resistance caused by T790M mutation irrespective of the drug concentrations. It is still the most important mechanism accounting for 30–50% of the resistance both in reversible EGFR-TKIs naive patients and treated patients according to the rencent studies. [18, 19]. (Table 2) But the phase II B lux-lung 7 (NCT01466660) study indicated that afatinib significantly prolonged the progression-free survival (PFS)
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