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Genomic aberrations associated with erlotinib resistance in non-small cell lung cancer cells

Masakuni Serizawa1, Toshiaki Takahashi, Nobuyuki Yamamoto

  • 1Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, 1007 Shimonagakubo Nagaizumi-cho Sunto-gun, Shizuoka, 411-8777, Japan. y.koh@scchr.jp.

Anticancer Research
|December 11, 2013
PubMed
Abstract

Insights

Acquired CRKL amplification contributes to resistance against epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). This discovery aids in understanding and potentially overcoming TKI resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mechanisms of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) remain incompletely understood.
  • Erlotinib-resistant NSCLC cell lines were utilized to investigate novel resistance pathways.

Purpose of the Study:

  • To elucidate unknown mechanisms of resistance to EGFR-TKIs in NSCLC.
  • To identify genomic alterations associated with erlotinib resistance in NSCLC cells.

Main Methods:

  • Array comparative genomic hybridization (aCGH) was performed on erlotinib-resistant PC-9ER cells.
  • Real-time polymerase chain reaction (PCR) and immunoblot analyses were used to validate aCGH findings.

Main Results:

  • Copy number gain in the 22q11.2-q12.1 region, including CRKL (v-crk avian sarcoma virus CT10 oncogene homolog-like), was identified in PC-9ER cells.
  • Overexpression of CRKL was associated with EGFR-TKI resistance.
  • Inhibition of phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway suppressed proliferation in resistant cells, suggesting CRKL amplification's role.

Conclusions:

  • Acquired CRKL amplification is a newly identified mechanism contributing to EGFR-TKI resistance in NSCLC.
  • The developed erlotinib-resistant cell line model is valuable for further research into TKI resistance mechanisms.
Keywords:
CRKLEGFR-TKI resistanceamplificationcopy-number alterationerlotinibnon-small cell lung cancer

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