title: Overexpression of DDX43 mediates MEK inhibitor resistance through RAS Upregulation in uveal melanoma cells.
abstract: The majority of uveal melanomas carry oncogenic mutations in the G proteins GNAQ and GNA11, with consequent activation of the MAPK pathway. Selective MEK inhibitors, such as selumetinib, have shown clinical benefit in uveal melanoma. However, mechanisms of drug resistance limit their efficacy in some patients. Analysis of MEK inhibitor-resistant uveal melanoma cell lines revealed the induction of RAS protein expression and activity. This effect was mediated by the RNA helicase DDX43, which was remarkably overexpressed in these cells. Depletion of DDX43 in MEK inhibitor-resistant cells decreased RAS proteins and inhibited ERK and AKT pathways. On the contrary, ectopic expression of DDX43 in parental uveal melanoma cells induced RAS protein levels and rendered cells resistant to MEK inhibition. Similar to DDX43 depletion, downregulation of KRAS, HRAS, and NRAS inhibited downstream pathways in the resistant cells, overcoming mutant GNAQ signaling. We also analyzed the expression of DDX43 in liver metastases of patients with uveal melanoma by RT-PCR, and found a significant overexpression of DDX43 in patients who did not benefit from selumetinib therapy. In conclusion, DDX43 induces RAS protein expression and signaling, mediating a novel mechanism of MEK inhibitor resistance. The detection of DDX43 in patients with uveal melanoma could lead to more targeted therapies for this disease.
authors.affiliation: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine; ga2391@columbia.edu.
authors.forename: Grazia
authors.initials: G
authors.lastname: Ambrosini
authors.affiliation: Department of Bioinformatics, Memorial Sloan-Kettering Cancer Center; and.
authors.forename: Raya
authors.initials: R
authors.lastname: Khanin
authors.affiliation: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine;
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000556:secondary; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology* / Q000556:secondary; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation; D014604:Uveal Neoplasms / Q000201:enzymology* / Q000473:pathology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; C412324:DDX43 protein, human; D053487:DEAD-box RNA Helicases; D018631:ras Proteins