Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts

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• 作者：Giovanni Sette (7)
  Katia Fecchi (6)
  Valentina Salvati (6)
  Fiorenza Lotti (6)
  Emanuela Pilozzi (8)
  Enrico Duranti (8)
  Mauro Biffoni (6)
  Alfredo Pagliuca (6)
  Daniela Martinetti (9)
  Lorenzo Memeo (9)
  Michele Milella (7)
  Ruggero De Maria (7)
  Adriana Eramo (6)
  
• 关键词：Metastatic Melanoma ; Mek inhibition ; Melanospheres ; Target therapy
• 刊名：Journal of Experimental & Clinical Cancer Research
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：32
• 期：1
• 全文大小：1,891 KB
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• 作者单位：Giovanni Sette (7)
  Katia Fecchi (6)
  Valentina Salvati (6)
  Fiorenza Lotti (6)
  Emanuela Pilozzi (8)
  Enrico Duranti (8)
  Mauro Biffoni (6)
  Alfredo Pagliuca (6)
  Daniela Martinetti (9)
  Lorenzo Memeo (9)
  Michele Milella (7)
  Ruggero De Maria (7)
  Adriana Eramo (6)
  
  7. Regina Elena National Cancer Institute, Rome, Italy
  6. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanit脿, viale Regina Elena 299, Rome, 00161, Italy
  8. Department of Clinical and Molecular Medicine, Sant鈥橝ndrea Hospital, University 鈥楲a Sapienza鈥? Rome, Italy
  9. Mediterranean Institute of Oncology, Catania, Italy
  
• ISSN：1756-9966

文摘

One of the key oncogenic pathways involved in melanoma aggressiveness, development and progression is the RAS/BRAF/MEK pathway, whose alterations are found in most patients. These molecular anomalies are promising targets for more effective anti-cancer therapies. Some Mek inhibitors showed promising antitumor activity, although schedules and doses associated with low systemic toxicity need to be defined. In addition, it is now accepted that cancers can arise from and be maintained by the cancer stem cells (CSC) or tumor-initiating cells (TIC), commonly expanded in vitro as tumorspheres from several solid tumors, including melanoma (melanospheres). Here, we investigated the potential targeting of MEK pathway by exploiting highly reliable in vitro and in vivo pre-clinical models of melanomas based on melanospheres, as melanoma initiating cells (MIC) surrogates. MEK inhibition, through PD0325901, provided a successful strategy to affect survival of mutated-BRAF melanospheres and growth of wild type-BRAF melanospheres. A marked citotoxicity was observed in differentated melanoma cells regardless BRAF mutational status. PD0325901 treatment, dramatically inhibited growth of melanosphere-generated xenografts and determined impaired tumor vascularization of both mutated- and wild type-BRAF tumors, in the absence of mice toxicity. These results suggest that MEK inhibition might represent a valid treatment option for patients with both mutated- or wild type-BRAF melanomas, affecting tumor growth through multiple targets.