Towards combinatorial targeted therapy in melanoma: From pre-clinical evidence to clinical application (Review)

Abstract

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.

Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma

“…Activation of one or both RAS/ERK and PI3K/AKT/ mTOR pathways in the majority of MM from both humans and dogs examined overlaps with the pattern of similar activation in well-documented cutaneous melanomas and other cancers (Bogenrieder and Herlyn, 2010;Fowles et al, 2015;Grazia et al, 2014;Karbowniczek et al, 2008;Margolin et al, 2012). The RAS/ERK and the PI3K/AKT/mTOR pathways are known to intersect with variable feedback and regulatory influences overlapping downstream (Ersahin et al, 2015;Mendoza et al, 2011;Shi et al, 2011;Van Dort et al, 2015).…”

A novel molecular disease classifier for psoriasis and eczema

“…Over the past years, the list of new specific therapeutic agents and candidate molecules for target‐oriented therapies in the field of inflammatory skin diseases has broadly increased . In contrast to melanoma research, for example, where the development of new therapeutic agents is paralleled by the establishment of diagnostic markers and risk prediction models enabling to choose the most efficient therapy according to the patient's individual disease signature, approved diagnostic systems and biomarkers have not yet been established for psoriasis and eczema. Currently, this becomes a major issue, as now various specific therapies for patients with inflammatory skin diseases are available.…”

Resistance of melanoma cells to anticancer treatment: a role of vascular endothelial growth factor

“…Cell apoptosis is controlled by numerous signalling pathways and the most important ones are: external (via receptors) and internal (via mitochondria) [76,77]. The external pathway is triggered by binding appropriate ligands (TNF-α, CD95L/FasL or TRAIL) to death receptors.…”