Malignant melanoma is the most aggressive and life-threatening skin cancer.
Melanoma develops in melanocytes and is characterized by a very high tendency to spread to
other parts of the body. Its pathogenesis depends on DNA mutations leading to the activation
of oncogenes or to the inactivation of suppressor genes. The identification of misregulations
in intracellular signal transduction pathways has provided an opportunity for the development
of mutation-specific inhibitors, which specifically target the mutated signaling cascades. Over
the last few years, clinical trials with MAPK pathway inhibitors have shown significant clinical
activity in melanoma; however, their efficacy is limited due to the onset of acquired resistance.
This has prompted a large set of preclinical studies looking at new approaches of pathway-
or target-specific inhibitors. This review gives an overview of the latest developments of
small molecule targeting multiple molecular pathways in both preclinical and clinical melanoma
settings, with particular emphasis on additional strategies to tackle the reduced responsiveness
to inhibitor treatment as possible future directions.
Keywords: Melanoma, metastasis, small molecules, targeted therapies, drug-resistance, MAPK pathway, cell cycle
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