New perspectives for targeting RAF kinase in human cancer

Abstract

The discovery that a subset of human tumours is dependent on mutationally deregulated BRAF kinase intensified the development of RAF inhibitors to be used as potential therapeutics. The US Food and Drug Administration (FDA)-approved second-generation RAF inhibitors vemurafenib and dabrafenib have elicited remarkable responses and improved survival of patients with BRAF-V600E/K melanoma, but their effectiveness is limited by resistance. Beyond melanoma, current clinical RAF inhibitors show modest efficacy when used for colorectal and thyroid BRAF-V600E tumours or for tumours harbouring BRAF alterations other than the V600 mutation. Accumulated experimental and clinical evidence indicates that the complex biochemical mechanisms of RAF kinase signalling account both for the effectiveness of RAF inhibitors and for the various mechanisms of tumour resistance to them. Recently, a number of next-generation RAF inhibitors, with diverse structural and biochemical properties, have entered preclinical and clinical development. In this Review, we discuss the current understanding of RAF kinase regulation, mechanisms of inhibitor action and related clinical resistance to these drugs. The recent elucidation of critical structural and biochemical aspects of RAF inhibitor action, combined with the availability of a number of structurally diverse RAF inhibitors currently in preclinical and clinical development, will enable the design of more effective RAF inhibitors and RAF-inhibitor-based therapeutic strategies, tailored to different clinical contexts.

BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association

“…These inhibitors have been characterized based on their ability to inhibit signaling or growth of BRAF V600E ΔEx-harboring cells to infer their ability to inhibit BRAF dimers (Peng et al, 2015; Yao et al, 2015). Our data suggest that the effectiveness of these RAF inhibitors in this model system may additionally relate to their ability to disrupt BRAF-MEK association or sequester BRAF-MEK in an inactive conformation (Haling et al, 2014; Karoulia et al, 2017). Furthermore, although the disruption of BRAF dimerization has been associated with favorable results in preclinical models (Freeman et al, 2013; Grasso et al, 2016; Sieved: et al, 2013), directly testing how these treatments effect substrate binding is necessary to broadly apply such strategies.…”

“…It has been postulated that resistance to αC-OUT/DFG-IN RAF inhibitors, such as PLX4720 and vemurafenib, occurs via a mechanism whereby RAF dimers permit inhibitor binding to one protomer that precludes inhibitor binding to the second protomer(Karouliaet al, 2016,2017). In our study, BRAF V600E ΔEx protein homodimerization or oligomerization was disrupted at RAF inhibitor concentrations that failed to alter ERK1/2 pathway activity or cell growth.…”

“…New RAF inhibitors with distinct modes of action continue to enter clinical trials (Karoulia et al, 2017). These inhibitors have been characterized based on their ability to inhibit signaling or growth of BRAF V600E ΔEx-harboring cells to infer their ability to inhibit BRAF dimers (Peng et al, 2015; Yao et al, 2015).…”

c-Raf in KRas Mutant Cancers: A Moving Target

“…Indeed, the first c-Raf inhibitor to enter clinical trials, sorafenib, failed to make an impact on the Ras-driven cancers for which it was intended. Later, vemurafenib produced dramatic responses in B-Raf-driven melanoma but also failed in Ras mutant cancers (reviewed in Karoulia et al, 2017). Most unexpectedly, these inhibitors, along with other, more potent and selective, Raf inhibitors, were shown to induce rather than inhibit Raf kinase activity, both in Ras-driven cancers and, to a lesser extent, in normal cells.…”

Integrating clinical, molecular, proteomic and histopathological data within the tissue context: tissunomics

“…Tumours with somatic mutations such as BRAF, EGFR or gene rearrangements such as ALK are considered therapeutic options regardless of tumour type or location, and tumours may even be characterised as BRAFomas or ALKomas. However, some clinical data have shown that, while BRAF inhibitors are effective in melanoma, the same inhibitors of the same BRAF mutations in colorectal cancer induce feedback loops in signalling pathways that can have a detrimental effect . Cell signalling pathways are also highly regulated, often dependent on numerous positive and negative feedback loops, which are specific to the cell type and tumour environment.…”