Identification of a novel partner gene, KIAA1217, fused to RET: Functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma

Oncotarget. 2016 Jun 14;7(24):36101-36114. doi: 10.18632/oncotarget.9137.

Abstract

REarranged during Transfection (RET) fusion genes are detected in approximately 1% of lung adenocarcinomas and known primarily as oncogenic driver factors. Here, we found a novel RET fusion gene, KIAA1217-RET, and examined the functional differences of RET51 and RET9 protein, fused with KIAA1217 in cancer progression and drug response. KIAA1217-RET, resulting from the rearrangement of chromosome 10, was generated by the fusion of KIAA1217 exon 11 and RET exon 11 from a non-small cell lung cancer patient. Expression of this gene led to increased cell growth and invasive properties through activations of the PI3K/AKT and ERK signaling pathways and subsequently enabled oncogenic transformation of lung cells. We observed that cells expressing KIAA1217-RET9 fusion protein were more sensitive to vandetanib than those expressing KIAA1217-RET51 and both isoforms attenuated cellular growth via cell cycle arrest. These results demonstrated that KIAA1217-RET fusion represents a novel oncogenic driver gene, the products of which are sensitive to vandetanib treatment, and suggested that the KIAA1217-RET-fusion gene is a promising target for lung cancer treatment.

Keywords: KIAA1217; KIAA1217-RET fusion; RET; lung cancer; oncogenic driver.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • NIH 3T3 Cells
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Piperidines / pharmacology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proteins / genetics*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-ret / genetics*
  • Proto-Oncogene Proteins c-ret / metabolism
  • Quinazolines / pharmacology
  • Transplantation, Heterologous

Substances

  • KIAA1217 protein, human
  • Oncogene Proteins, Fusion
  • Piperidines
  • Protein Isoforms
  • Proteins
  • Quinazolines
  • Proto-Oncogene Proteins c-ret
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine