A New Era of Proactive Melanoma Therapy: Hit Hard, Hit Early

L. Haas; T. Wiesner; A. C. Obenauf


The British Journal of Dermatology. 2018;178(4):817-820. 

In This Article

Targeted Therapy

Targeted therapies specifically act on aberrantly activated pathways in cancer cells. Approximately 50% of melanomas harbour oncogenic BRAF V600E/K mutations, which constitutively activate the mitogen–activated protein kinase (MAPK) pathway. The activated MAPK pathway sustains tumour cell survival and proliferation, and instructs the tumour microenvironment to an immunosuppressive state (Figure 1).[6] Targeted therapies with small molecules inhibiting mutated BRAF (RAFi, for example, vemurafenib or dabrafenib) induce tumour regression in the majority of patients with BRAF–mutated melanoma, and quickly became a therapeutic cornerstone for metastatic melanoma.[7]

However, the majority of tumours acquire resistance and bypass the therapeutic RAFi inhibition by re–activating the MAPK pathway through various genetic and epigenetic mechanisms. To prevent the re–activation of the MAPK pathway and therapy resistance, small molecules inhibiting a central protein in the MAPK pathway downstream of BRAF, termed MAPK kinase (MEK), were included in the treatment regimen (MEKi, for example cobimetinib or trametinib). The dual inhibition of the MAPK pathway with RAFi and MEKi, indeed, delayed the development of resistance in melanoma and became the new standard of care.[8] However, the progression–free survival increased only marginally from 6 to 9 months[7] with RAFi as a single agent, to approximately 11 months[8] with dual RAFi and MEKi inhibition.

In summary, these data indicate that tumours that are both genetically and epigenetically unstable, and thus constantly evolving and adapting to therapeutic selection pressures, are difficult to control with targeted therapy alone. This is particularly true for patients with a high tumour burden and late stages of tumour evolution,[9,10] arguing for an earlier start of therapy (Figure 2).