Mek inhibition results in marked antitumor activity against metastatic melanoma patient-derived melanospheres and in melanosphere-generated xenografts.
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.
Giovanni
G
Sette
Katia
K
Fecchi
Valentina
V
Salvati
Fiorenza
F
Lotti
Emanuela
E
Pilozzi
Enrico
E
Duranti
Mauro
M
Biffoni
Alfredo
A
Pagliuca
Daniela
D
Martinetti
Lorenzo
L
Memeo
Michele
M
Milella
Ruggero
R
De Maria
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome 00161, Italy. adriana.eramo@iss.it.
Adriana
A
Eramo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D018874:Spheroids, Cellular; D023041:Xenograft Model Antitumor Assays
D001549:Benzamides; D047428:Protein Kinase Inhibitors; C506614:mirdametinib; D004159:Diphenylamine; D020930:MAP Kinase Kinase Kinases