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.