Research Progresses Of Resistance Mechanisms And Therapeutic Strategies For Patients With Non-small Cell Lung Cancer After Acquired Resistance To EGFR-TKIs

The erbB family are composed of HER1(erbB1, EGFR), HER2(erbB2,NEU), HER3(erbB3), and HER4(erbB4). These cell-membrane receptors include anextracellular domain containing a ligand-binding pocket and an intracellular catalyticdomain. With binding of extracellular growth-factor ligands causes dimerization ofthe receptors, which leads to homo-or heterodimers. Formation of these dimers canactivate the receptors’ tyrosine kinase activity, and lead to intracellular signalingcascades. The epidermal growth factor receptor (EGFR) tyrosine kinases control theintracellular signaling pathways that promote cell growth, proliferation, differentiation,and migration. The non-small cell lung cancer (NSCLC) with activating EGFRmutations is now a well-described molecular subgroup of NSCLC. Multipleaberrations in the signal-transduction pathways controlled by EGFR have beenimplicated in NSCLC. For example, mutations in genes which encode EGFR pathwayproteins result in dysregulation of the proteins’ tyrosine kinase activity and lead toproliferation, survival, and dissemination of malignant cells. Some specificEGFR-activating mutations have been identified, which include single nucleotidemutations, in-frame duplications/insertions, and single-nucleotide substitutions. Themost common EGFR mutations in patients with NSCLC are deletions in exon19anda single amino acid substitution in exon21-L858R. These mutations are locatedwithin the catalytic domain and lead to EGFR activation. There are evidences thatNSCLC with EGFR-activating mutations become completely dependent on EGFR toactivate downstream intracellular signaling cascades. The activity of tyrosine kinasecan be inhibited by epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), which will interrupt downstream signaling cascades and the NSCLC cells are unable to replicate and undergo apoptosis. The first-generation EGFR-TKIs,including erlotinib and gefitinib, bind reversibly to the kinase domain and effectivelyinhibit mutated EGFR. There are evidences that patients with NSCLC and activatingEGFR mutations have unique sensitivity to targeted therapy with EGFR-TKIs, withresponse rate (RR) around75%in the first-line setting.At the present time, erlotiniband gefitinib are approved for use in the first-line treatment of patients with advancedNSCLC and EGFR-activating mutations, and can also be used in second-andthird-line treatment for all patients with NSCLC, regardless of EGFR mutation status,even as maintenance treatment. These first-generation EGFR-TKIs can improveprogression-free survival (PFS) in the first-line treatment of patients with advancedNSCLC and EGFR-activating mutations compared to chemotherapy. However, theseEGFR-mutated patients eventually develop resistance to EGFR-TKIs after a medianof10-14months on an EGFR-TKI. The finding that the mechanisms of acquiredresistance, such as the T790M mutation, amplification of the MET oncogene, andphenotypic transformation, provides the rationale to develop new generation agentstargeting the underlying molecular mechanisms to overcome acquired resistance toEGFR-TKIs. While these new generation agents can not be put into clinical practicecompletely at the present time, they augment more holp to therapy patients withNSCLC. Thus, there is a need for therapy options for patients with NSCLC afteracquired resistance to EGFR-TKIs at present, which we must confront in clinicalpractice. According to the present problem, this literature refers to relational database,to find the literatures about the mechanisms of acquired resistance to EGFR-TKIs andsequential treatment in patients with NSCLC. By comparion and generalization ofthese datas, this literature desires to offer some prompts for the research of preclinicaland clinical practice.