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- July 18, 2013 at 3:57 pm
Commentary
Journal of Investigative Dermatology (2013) 133, 1928–1929; doi:10.1038/jid.2013.136
A STATement on Vemurafenib-Resistant Melanoma
Edward J Hartsough1 and Andrew E Aplin1
Commentary
Journal of Investigative Dermatology (2013) 133, 1928–1929; doi:10.1038/jid.2013.136
A STATement on Vemurafenib-Resistant Melanoma
Edward J Hartsough1 and Andrew E Aplin1
1Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
Correspondence: Edward J. Hartsough or Andrew E. Aplin, Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA. E-mail: ejh004@Jefferson.edu or Andrew.Aplin@Jefferson.edu
Abstract
Despite recent advancements in the treatment of late-stage mutant BRAF V600E/K melanomas, a major hurdle continues to be acquired resistance to BRAF inhibitors such as vemurafenib. The mechanisms for resistance have proven to be heterogeneous, emphasizing the need to use broad therapeutic approaches. In this issue, the study “Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas” by Liu et al. proposes that signal transducer and activator of transcription 3 (STAT3)–paired box 3 (PAX3) signaling may be a mechanism that is used by melanomas to resist RAF inhibitors.
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Original Article
Subject Category: Melanocytes/Melanoma
Journal of Investigative Dermatology (2013) 133, 2041–2049; doi:10.1038/jid.2013.32; published online 28 February 2013
Stat3-Targeted Therapies Overcome the Acquired Resistance to Vemurafenib in Melanomas
Fang Liu1,2,5, Juxiang Cao1,5, Jinxiang Wu1, Kayleigh Sullivan1, James Shen1, Byungwoo Ryu1, Zhixiang Xu3, Wenyi Wei4 and Rutao Cui1
- 1Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts, USA
- 2Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- 3Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
- 4Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
Correspondence: Fang Liu, Department of Dermatology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, China. E-mail: roseliufang@hotmail.com; Rutao Cui, Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, Massachusetts 02478, USA. E-mail: rutaocui@bu.edu
5These authors contributed equally to this work.
Received 3 August 2012; Revised 19 December 2012; Accepted 1 January 2013
Accepted article preview online 23 January 2013; Advance online publication 28 February 2013Abstract
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 BrafV600E 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 BrafV600E 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.
Abbreviations:
FGF, fibroblast growth factor; PAX3, paired box homeotic gene 3
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