title: Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma.
abstract: We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of the resistant tumors in immunocompromised mice. Our data show that BRAF inhibitor-mediated activation of EGFR-SFK-STAT3 signaling can mediate resistance in patients with BRAF-mutant melanoma. We describe 2 treatments that seem to overcome this resistance and could deliver therapeutic efficacy in patients with drug-resistant BRAF-mutant melanoma.
  
  
  CONCLUSIONS
  Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratified for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF -mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients.
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, Royal Marsden Hospital, London, UK.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Girotti
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.forename: Berta
authors.initials: B
authors.lastname: Sanchez-Laorden
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.forename: Samra
authors.initials: S
authors.lastname: Turajlic
authors.forename: Dan
authors.initials: D
authors.lastname: Niculescu-Duvaz
authors.forename: Alfonso
authors.initials: A
authors.lastname: Zambon
authors.forename: John
authors.initials: J
authors.lastname: Sinclair
authors.forename: Andrew
authors.initials: A
authors.lastname: Hayes
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.forename: Paul
authors.initials: P
authors.lastname: Lorigan
authors.forename: Caroline
authors.initials: C
authors.lastname: Springer
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Claus
authors.initials: C
authors.lastname: Jorgensen
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D013844:Thiazoles; D000077484:Vemurafenib; D066246:ErbB Receptors; D019061:src-Family Kinases; D048493:Proto-Oncogene Proteins B-raf; D000069439:Dasatinib