title: Genomic aberrations associated with erlotinib resistance in non-small cell lung cancer cells.
abstract: OBJECTIVE
  Mechanisms of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are not fully-understood. In this study we aimed to elucidate remaining unknown mechanisms using erlotinib-resistant NSCLC cells.
  
  
  METHODS
  We performed array comparative genomic hybridization (aCGH) to identify genomic aberrations associated with EGFR-TKI resistance in erlotinib-resistant PC-9ER cells. Real-time polymerase chain reaction (PCR) and immunoblot analyses were performed to confirm the results of aCGH.
  
  
  RESULTS
  Among the five regions with copy number gain detected in PC-9ER cells, we focused on 22q11.2-q12.1 including v-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL), the overexpression of which seemed to be associated with EGFR-TKI resistance. Blockade of downstream phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT) signaling using NVP-BEZ235 suppressed the proliferation of PC-9ER cells, implying the involvement of acquired CRKL amplification in EGFR-TKI resistance.
  
  
  CONCLUSIONS
  Acquired CRKL amplification was identified as contributing to EGFR-TKI resistance; this cell line model can be utilized to study this resistance mechanism.
authors: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo Nagaizumi-cho Sunto-gun, Shizuoka, 411-8777, Japan. y.koh@scchr.jp.
authors: Masakuni
authors: M
authors: Serizawa
authors: Toshiaki
authors: T
authors: Takahashi
authors: Nobuyuki
authors: N
authors: Yamamoto
authors: Yasuhiro
authors: Y
authors: Koh
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011799:Quinazolines / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride
keywords: CRKL; EGFR-TKI resistance; amplification; copy-number alteration; erlotinib; non-small cell lung cancer