title: Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer.
abstract: BACKGROUND
  Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations.
  
  
  METHODS
  Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry.
  
  
  RESULTS
  Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis.
  
  
  CONCLUSIONS
  The mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary.
authors.forename: Wonjun
authors.initials: W
authors.lastname: Ji
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Choi
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Rho
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jang
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Park
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Chun
authors.forename: Woo Sung
authors.initials: WS
authors.lastname: Kim
authors.forename: Jung-Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Seoul, Songpa-gu, Korea. jclee@amc.seoul.kr.
authors.forename: Jae Cheol
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011379:Prognosis; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D056910:Republic of Korea; D012189:Retrospective Studies; D017384:Sequence Deletion; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib