《综述：二代egfr抑制剂bibwpf三代的三个资料》由会员分享，可在线阅读，更多相关《综述：二代egfr抑制剂bibwpf三代的三个资料（10页珍藏版）》请在金锄头文库上搜索。
1、Drug Resistance to EGFR Tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer Kazuhiko Shiena,b, Hiromasa Yamamotob, Junichi Sohb, Shinichiro Miyoshib, and Shinichi Toyookaa,b Departments of aClinical Genomic Medicine, and bGeneral Thoracic Surgery and Breast and Endocrinological Surgery, Okayam
2、a University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan Non-small cell lung cancer (NSCLC) harboring an activating mutation within the epidermal growth factor receptor (EGFR) was defi ned as a clinically distinct molecular group. These lesions show on
3、co- gene addiction to EGFR and dramatic responses to the EGFR tyrosine kinase inhibitors (TKIs). Several large Phase III trials have shown that EGFR-TKIs improved the progression-free survival of patients with EGFR mutant NSCLC compared to conventional chemotherapy. However, the long-term eff ective
4、ness of EGFR-TKIs is usually limited because of acquired drug resistance. To overcome this resistance to EGFR-TKIs, it will be essential to identify the specifi c mechanisms underlying the resis- tance. Many investigators have attempted to identify the mechanisms using preclinical models and drug-re
5、sistant clinical samples. As a result, several mechanisms have been showed to be responsible for the resistance, but not all of the relevant mechanisms have been uncovered. In this review, we provide an overview of mechanisms underlying drug-resistance to EGFR-TKIs, focusing on results obtained with
6、 preclinical models, and we present some possible strategies to overcome the EGFR-TKI resistance. Key words: non-small cell lung cancer, EGFR mutation, tyrosine-kinase inhibitor, drug resistance, cancer stem cell ung cancer continues to be the leading cause of death among patients with malignant tum
7、ors worldwide 1. Many patients are diagnosed after the cancer has already spread to distant sites or directly beyond the primary site, resulting in an inoperable stage. In 2004, mutations in the epidermal growth factor receptor (EGFR) that cause oncogene addiction to EGFR were discovered in non-smal
8、l cell lung can- cer (NSCLC) 2, 3. Because these mutations are strongly associated with sensitivity to EGFR-tyrosine kinase inhibitors (TKIs), a great deal of knowledge has been uncovered in regard to both EGFR and other genes in the EGFR family and their downstream genes. EGFR-TKIs have exhibited s
9、ignifi cant antiprolif- erative eff ects against NSCLC with EGFR-activating mutations in preclinical studies 2, 3 and their use in the treatment of NSCLC patients has also resulted in prolonged progression-free survival (PFS) in random- ized Phase III studies 4-7. However, patients with EGFR mutatio
10、ns who initially respond to EGFR-TKIs eventually acquire resistance, which is a critical problem in the treatment of patients with advanced L Acta Med. Okayama, 2014 Vol. 68, No. 4, pp. 191200 Copyright 2014 by Okayama University Medical School. Review http :/ /escholarship.lib.okayama-u.ac.jp/amo/
11、Received February 25, 2014 ; accepted June 12, 2014. Corresponding author. Phone : 81862357436; Fax : 81862357437 E-mail : toyookamd.okayama-u.ac.jp (S. Toyooka) Confl ict of Interest Disclosures: No potential confl ict of interest relevant to this article was reported. NSCLC. Several mechanisms are
12、 believed to be responsible for intrinsic and acquired resistance to EGFR-TKIs, including secondary EGFR T790M and minor mutations, MET amplifi cation, and activation of the MET/HGF axis, acquiring an epithelial to mesen- chymal transition (EMT) signature, and transforma- tion from NSCLC into small
13、cell lung cancer (SCLC) 8-13. More recently, AXL kinase activation, loss of the EGFR-mutant allele, and emergence of cancer- stem cell (CSC)-like properties have been reported as possible mechanisms of resistance 14-16. However, it is likely that additional mechanisms remain to be identifi ed. In th
14、is review, we focus on the NSCLCs harboring EGFR-activating mutations, and we summarize the mechanisms of drug sensitivity and resistance to EGFR-TKIs. We also describe some possible molecu- larly targeted strategies for further improving the outcomes of NSCLC patients with EGFR-activating mutations
15、. EGFR-activating Mutations in NSCLC EGFR (ErbB1) is a member of the ErbB trans- membrane receptor family, which includes ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). These receptors have similar structures and consist of three domains: an extracellular domain, a transmem- brane domain, and an
16、intracellular domain. The extracellular domain has a ligand-biding region, and several ligands including EGF bind here. The ligand binding causes receptor homo- or hetero-dimerization between EGFR and other ErbB family members at the cell surface, followed by internalization of the dimerized receptor. The receptor dimerization results in auto- phosphorylation of the intracellular EGFR tyrosine kinase domain. Subsequently, the phosphorylated tyrosine kinase stimulat
