title: A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation.
abstract: Targeting cancers with amplified or abnormally activated c-Met (hepatocyte growth factor receptor) may have therapeutic benefit based on nonclinical and emerging clinical findings. However, the eventual emergence of drug resistant tumors motivates the pre-emptive identification of potential mechanisms of clinical resistance. We rendered a MET amplified gastric cancer cell line, GTL16, resistant to c-Met inhibition with prolonged exposure to a c-Met inhibitor, PF-04217903 (METi). Characterization of surviving cells identified an amplified chromosomal rearrangement between 7q32 and 7q34 which overexpresses a constitutively active SND1-BRAF fusion protein. In the resistant clones, hyperactivation of the downstream MAPK pathway via SND1-BRAF conferred resistance to c-Met receptor tyrosine kinase inhibition. Combination treatment with METi and a RAF inhibitor, PF-04880594 (RAFi) inhibited ERK activation and circumvented resistance to either single agent. Alternatively, treatment with a MEK inhibitor, PD-0325901 (MEKi) alone effectively blocked ERK phosphorylation and inhibited cell growth. Our results suggest that combination of a c-Met tyrosine kinase inhibitor with a BRAF or a MEK inhibitor may be effective in treating resistant tumors that use activated BRAF to escape suppression of c-Met signaling.
authors: Oncology Research Unit, Pfizer Global Research & Development, San Diego, California, United States of America.
authors: Nathan V
authors: NV
authors: Lee
authors: Maruja E
authors: ME
authors: Lira
authors: Adam
authors: A
authors: Pavlicek
authors: Jingjing
authors: J
authors: Ye
authors: Dana
authors: D
authors: Buckman
authors: Shubha
authors: S
authors: Bagrodia
authors: Sreesha P
authors: SP
authors: Srinivasa
authors: Yongjun
authors: Y
authors: Zhao
authors: Samuel
authors: S
authors: Aparicio
authors: Paul A
authors: PA
authors: Rejto
authors: James G
authors: JG
authors: Christensen
authors: Keith A
authors: KA
authors: Ching
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C558663:2-(4-(3-quinolin-6-ylmethyl-3H-(1,2,3)triazolo(4,5-b)pyrazin-5-yl)pyrazol-1-yl)ethanol; D009687:Nuclear Proteins; D011719:Pyrazines; D011993:Recombinant Fusion Proteins; D014230:Triazoles; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D004720:Endonucleases; C095221:SND1 protein, human