BRAF: Novel Therapies for an Emerging Target

Driver mutations in the BRAF oncogene occur in 2–4% of non-small cell lung cancers (NSCLC). Approximately half of these BRAF mutations are characterized by a glutamic acid substitution for valine at position 600 within the BRAF kinase domain (V600E or class I). The remaining non-V600E mutations are a heterogeneous group that can be further subdivided into mutations that activate BRAF kinase activity (class II) and mutations that remain dependent on upstream signaling through Ras-GTPase (class III). In normal cells, the BRAF kinase functions as an intermediary within the MAPK/ERK signaling pathway. Activating mutations in the BRAF oncogene lead to downstream signaling through the MAPK/ERK pathway, resulting in an increased risk of malignant transformation in preclinical models. Based on these findings, as well as the need for more effective treatment options for patients with BRAF-mutated NSCLC, there has been a significant interest in developing targeted therapies to inhibit the MAPK/ERK pathway. In a series of phase 2 clinical trials enrolling patients with metastatic BRAF V600E-mutated NSCLC, Planchard et al. established a role for combined BRAF and MEK tyrosine kinase inhibition (TKI) with dabrafenib and trametinib, respectively. While this represents an important new treatment strategy, a number of questions still remain including how best to sequence targeted therapy with other available treatment options and how to effectively overcome acquired resistance to TKI therapy.