SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

Time: 11:15 am
day: Day One


  • PF-06939999 is a potent and selective S-adenosyl methionine competitive inhibitor of PRMT5 being explored in solid tumor tumors in a phase 1 study
  • PRMT5 inhibition by PF-06939999 treatment reduced the in vitro and in vivo proliferation of NSCLC cancer cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs.
  • Analysis of sensitivity to the inhibitor, across a panel of NSCLC cell lines, identified mutations in the splicing factor RBM10 that could be used as a predictive biomarker of response
  • Models of acquired drug resistance to SAM-competitive and peptidecompetitive PRMT5 inhibitors identified mutations in the PRMT5 enzyme unique to the binding mode for each compound and highlighted SAM- competitive inhibitors have less susceptibly to complete drug resistance.