Indeed, the BRAF activation cycle remains incompletely understood. This insight led to the development of clinical trials combining multiple targeted therapy compounds. Moreover, other tumor entities such as CRC do not display such uniform responses due to primary resistance caused by rapid reactivation of the EGFR pathway (Corcoran et al, 2012 Prahallad et al, 2012). Nevertheless, even initially responding BRAF mutant melanomas acquire drug resistance (Moriceau et al, 2015). Indeed, vemurafenib and dabrafenib have significantly improved the treatment options for metastatic melanoma harboring BRAF V600E/K mutations (Chapman et al, 2011 Hauschild et al, 2012) and similar outcomes may be achieved in other malignancies driven by BRAF V600E such as hairy cell leukemia (Dietrich et al, 2016). The clinically most advanced compounds, vemurafenib or dabrafenib, as well as the first RAF inhibitor sorafenib are ATP competitive drugs. SynopsisĬonsequently, BRAF has become an important therapeutic target in cancer (Holderfield et al, 2014 Turski et al, 2016), with other proliferative diseases such as RASopathies and polycystic kidney disease potentially following suit, as it has been suggested by animal models (Inoue et al, 2014 Chang et al, 2015). Thus, the quaternary structure of BRAF complexes is shaped by its activation status, the conformation of its kinase domain, and clinically relevant inhibitors. However, expression of oncogenic K‐Ras G12V, either by itself or in combination with RAF dimer promoting inhibitors, induces the incorporation of BRAF WT into large, active complexes, whereas pharmacological inhibition of BRAF V 600E has the opposite effect. Hyperactive BRAF V 600E resides in large complexes of higher molecular mass and activity, while BRAF WT is confined to smaller, slightly less active complexes. We identified two macromolecular, cytosolic BRAF complexes of distinct molecular composition and phosphorylation status. By applying SEC‐ PCP‐ SILAC, we analyzed protein–protein interactions of hyperactive BRAF V 600E and wild‐type BRAF ( BRAF WT).

Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. Consequently, it has emerged as an important therapeutic target in various malignancies. As a central element within the RAS/ ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors.

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