Ductal activation of oncogenic KRAS alone induces sarcomatoid phenotype.

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.

• Authors: Yong Fu, Zobeida Cruz-Monserrate, H Helen Lin, Yiyin Chung, Baoan Ji, Szu-Min Lin, Steven Vonderfecht, Craig D Logsdon, Chien-Feng Li, David K Ann
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 13347 (Aug 20 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26289340 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

• 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, pathology)
• Sarcoma (genetics, pathology)
• Signal Transduction (drug effects)
• Submandibular Gland (pathology)