TY - JOUR AB - Over the last few years, clinical trials with BRAF and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors have shown significant clinical activity in melanoma, but only a fraction of patients respond to these therapies, and development of resistance is frequent. This has prompted a large set of preclinical studies looking at several new combinatorial approaches of pathway- or target-specific inhibitors. At least five main drug association strategies have been verified in vitro and in preclinical models. The most promising include: i) vertical targeting of either MEK or phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) pathways, or their combined blockade; ii) association of receptor tyrosine kinases (RTKs) inhibitors with other pro-apoptotic strategies; iii) engagement of death receptors in combination with MEK-, mTOR/PI3K-, histone deacetylase (HDAC)-inhibitors, or with anti-apoptotic molecules modulators; iv) strategies aimed at blocking anti-apoptotic proteins belonging to B-cell lymphoma (Bcl-2) or inhibitors of apoptosis (IAP) families associated with MEK/BRAF/p38 inhibition; v) co-inhibition of other molecules important for survival [proteasome, HDAC and Signal transducers and activators of transcription (Stat)3] and the major pathways activated in melanoma; vi) simultaneous targeting of multiple anti-apoptotic molecules. Here we review the anti-melanoma efficacy and mechanism of action of the above-mentioned combinatorial strategies, together with the potential clinical application of the most promising studies that may eventually lead to therapeutic benefit. AD - Human Tumors Immunobiology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy AU - Grazia,Giulia AU - Penna,Ilaria AU - Perotti,Valentina AU - Anichini,Andrea AU - Tassi,Elena DA - 2014/09/01 DO - 10.3892/ijo.2014.2491 EP - 949 IS - 3 JO - Int J Oncol KW - melanoma combinatorial treatment targeted therapy apoptosis PY - 2014 SN - 1019-6439 1791-2423 SP - 929 ST - Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review) T2 - International Journal of Oncology TI - Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review) UR - https://doi.org/10.3892/ijo.2014.2491 VL - 45 ER -