Parallel and Serial Blockade Strategies in BRAF-Mutant Melanoma

Activating mutations in BRAF are the most common somatic aberration in cutaneous melanomas. These mutations result in constitutive activation of BRAF’s catalytic activity and its downstream effectors in the RAS-RAF-MEK-ERK signaling pathway. Both selective BRAF and MEK inhibitors have demonstrated high clinical response rates in metastatic melanoma patients with activating BRAF mutations. These successes have illustrated several keys to the successful development of targeted therapies, and the potential for personalized therapeutic strategies for cancer. However, the ultimate clinical benefit of BRAF and MEK inhibitors has been limited by both de novo and secondary resistance mechanisms. Initial preclinical and clinical studies support that these resistance mechanisms may broadly be characterized as those that result in (1) re-activation of the RAS-RAF-MEK-ERK signaling pathway, or (2) activation of other pro-survival mediators. These findings are now leading to the development of new combinatorial approaches that involve serial and/or parallel blockade strategies in order to overcome resistance mechanisms, and ultimately to improve outcomes in melanoma patients with activating BRAF mutations. Further, these concepts are also being explored and tested in melanoma patients with other oncogenic mutations.