Ductal activation of oncogenic KRAS alone induces sarcomatoid phenotype

Sci Rep. 2015 Aug 20:5:13347. doi: 10.1038/srep13347.

Abstract

Salivary duct carcinoma (SDC) is an uncommon, but aggressive malignant tumor with a high mortality rate. Herein, we reported the detection of somatic KRAS A146T and Q61H mutations in 2 out of 4 (50%) sarcomatoid SDC variants. Transgenic mice carrying the human oncogenic KRAS(G12V), which spatiotemporal activation by tamoxifen (TAM)-inducible Cre recombinase Ela-CreERT in the submandibular gland (SMG) ductal cells, was established and characterized. Visible carcinoma was detected as early as day-15 following oncogenic KRAS(G12V) induction alone, and these tumors proliferate rapidly with a median survival of 28-days accompanied with histological reminiscences to human sarcomatoid SDC variants. Moreover, these tumors were resistant to cetuximab treatment despite augmented EGFR signaling, attesting its malignancy. Our findings suggest that LGL-KRas(G12V);Ela-CreERT transgenic mice could serve as a useful preclinical model for investigating underlying mechanisms and developing potential therapies.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Proliferation
  • Cetuximab / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • ErbB Receptors / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Phenotype
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Salivary Ducts / pathology*
  • Salivary Gland Neoplasms / genetics*
  • Salivary Gland Neoplasms / pathology*
  • Sarcoma / genetics*
  • Sarcoma / pathology*
  • Signal Transduction / drug effects
  • Submandibular Gland / pathology

Substances

  • KRAS protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • Cetuximab