Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas.
Vemurafenib (PLX4032), a selective inhibitor of Braf, has been approved by the US Food and Drug Administration for the treatment of unresectable or metastatic melanoma in patients with Braf(V600E) mutations. Many patients treated with vemurafenib initially display dramatic improvement, with decreases in both risk of death and tumor progression. Acquired resistance, however, rapidly arises in previously sensitive cells. We attempted to overcome this resistance by targeting the signal transducer and activator of transcription 3 (STAT3)-paired box homeotic gene 3 (PAX3)-signaling pathway, which is upregulated, owing to fibroblast growth factor 2 (FGF2) secretion or increased kinase activity, with the Braf(V600E) mutation. We found that activation of Stat3 or overexpression of PAX3 induced resistance to vemurafenib in melanoma cells. In addition, PAX3 or Stat3 silencing inhibited the growth of melanoma cells with acquired resistance to vemurafenib. Furthermore, treatment with the Stat3 inhibitor, WP1066, resulted in growth inhibition in both vemurafenib-sensitive and -resistant melanoma cells. Significantly, vemurafenib stimulation induced FGF2 secretion from keratinocytes and fibroblasts, which might uncover, at least in part, the mechanisms underlying targeting Stat3-PAX3 signaling to overcome the acquired resistance to vemurafenib. Our results suggest that Stat3-targeted therapy is a new therapeutic strategy to overcome the acquired resistance to vemurafenib in the treatment of melanoma.
Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02478, USA. rutaocui@bu.edu
Fang
F
Liu
Juxiang
J
Cao
Jinxiang
J
Wu
Kayleigh
K
Sullivan
James
J
Shen
Byungwoo
B
Ryu
Zhixiang
Z
Xu
Wenyi
W
Wei
Rutao
R
Cui
D000970:Antineoplastic Agents / Q000494:pharmacology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D052816:Foreskin / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology; D000077484:Vemurafenib
D000970:Antineoplastic Agents; D007211:Indoles; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D020032:Tyrphostins; C519885:WP1066; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)