Targeting complex, adaptive responses in melanoma therapy.

Our understanding of the complex, adaptive mechanisms of response to targeted therapies in metastatic melanoma is now leading to more effective combination treatments. These include the simultaneous inhibition of signalling pathways and metabolic programmes, as well as epigenetic mechanisms or immunological checkpoints. We review the latest pre-clinical and clinical results of strategies to delay tumor progression through combination approaches, and also highlight some of the problems ahead, including patient stratification, the complexity of targeting adaptive responses, and the management of more severe toxicities that result from double and triple-drug treatments.