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

Journal of Experimental & Clinical Cancer Research

Adriana Eramo¹  Ruggero De Maria³  Michele Milella³  Lorenzo Memeo²  Daniela Martinetti²  Alfredo Pagliuca¹  Mauro Biffoni¹  Enrico Duranti⁴  Emanuela Pilozzi⁴  Fiorenza Lotti¹  Valentina Salvati¹  Katia Fecchi¹  Giovanni Sette³ 

[1] Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome 00161, Italy;Mediterranean Institute of Oncology, Catania, Italy;Regina Elena National Cancer Institute, Rome, Italy;Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, University ‘La Sapienza’, Rome, Italy

关键词: Target therapy;    Melanospheres;    Mek inhibition;    Metastatic Melanoma;   

Others  :  814203
DOI  :  10.1186/1756-9966-32-91

 received in 2013-08-28, accepted in 2013-11-13,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Sette et al.; licensee BioMed Central Ltd.

【 图 表 】

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