A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation.
PLoS One, 2012;7(6):e39653.
Lee NV[1], Lira ME, Pavlicek A, Ye J, Buckman D, Bagrodia S, Srinivasa SP, Zhao Y, Aparicio S, Rejto PA, Christensen JG, Ching KA
Affiliations
PMID: 22745804DOI: 10.1371/journal.pone.0039653
Impact factor: 3.752
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.
MeSH terms
Cell Line, Tumor; Drug Resistance, Neoplasm; Endonucleases; Humans; Mitogen-Activated Protein Kinases; Nuclear Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-met; Pyrazines; Recombinant Fusion Proteins; Triazoles
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