title: Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: sensitivity and resistance.
abstract: Gefitinib and erlotinib, which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), are highly effective against lung tumors with EGFR activating mutations. However, in 20-30% of cases, there is intrinsic resistance, and even if the treatment is effective, resistance is acquired in one to several years. Possible mechanisms of acquired resistance to EGFR-TKI, thus far, include a gatekeeper mutation of EGFR, activation of an alternate pathway, activation of EGFR downstream signals, transformation to small cell lung cancer, and epithelial-mesenchymal transition (EMT). Recently, BIM (BCL2L11), which is a BH3-only proapoptotic member of the Bcl-2 protein family, was shown to play a central role in inducing apoptosis in response to EGFR-TKI treatment in EGFR mutant lung cancer cells. Moreover, when the expression of active BIM protein was low, there was resistance to apoptosis induction by EGFR-TKI treatment and early disease progression. A polymorphism of the BIM gene unique to East Asian people has been detected and is now attracting attention as a factor causing resistance to EGFR-TKI due to decreased BIM activity.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan; Cancer Center, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan. Electronic address: takeuchi@staff.kanazawa-u.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan; Cancer Center, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D058990:Molecular Targeted Therapy; D009154:Mutation; D011110:Polymorphism, Genetic; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D011799:Quinazolines / Q000627:therapeutic use*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Acquired resistance; Apoptosis; BIM; EGFR mutation; EGFR-TKI