Novel RAF‐directed approaches to overcome current clinical limits and block the RAS/RAF node

Abstract

Mutations in the RAS–RAF–MEK–ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are also involved in cancer etiology. RAS proteins initiate the signaling cascade by promoting the dimerization of RAF kinases, which can act as oncoproteins as well: BRAFV600E is the most common oncogenic driver, mutated in the 8% of all malignancies. Research in this field led to the development of drugs that target the BRAFV600‐like mutations (Class I), which are now utilized in clinics, but cause paradoxical activation of the pathway and resistance development. Furthermore, they are ineffective against non‐BRAFV600E malignancies that dimerize and could be either RTK/RAS independent or dependent (Class II and III, respectively), which are still lacking an effective treatment. This review discusses the recent advances in anti‐RAF therapies, including paradox breakers, dimer‐inhibitors, immunotherapies, and other novel approaches, critically evaluating their efficacy in overcoming the therapeutic limitations, and their putative role in blocking the RAS pathway.

Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

“…The ERK1/2 cascade is activated by a wide range of stimuli including peptide growth factors such as epidermal growth factor (EGF) that bind to and activate receptor tyrosine kinases (RTKs). Activated RTKs recruit signalling proteins to the receptor, including adapter proteins such as GRB2 that bring other proteins to the complex like SOS, an exchange factor for RAS small G proteins (HRAS, KRAS and NRAS) [11,13]. RAS acts as a molecular switch for the system: it is inactive when bound to GDP and exchange of GDP for GTP, catalysed by exchange factors such as SOS, results in a conformational change and activation.…”

“…The drugs so far developed to target the ERK1/2 cascade are small molecule inhibitors, many of which target the ATP-binding site of the different protein kinases for inhibition. However, new approaches are being developed to increase specificity, avoid the RAF paradox effect of current RAF inhibitors, and reduce potential toxicity (see, for example, [13]). A key step forward in drug development is the use of PROTACs (proteolysis targeting chimeras) that combine a small molecule inhibitor of the protein of interest with an E3 ubiquitin ligase binder, resulting in ubiquitinylation of the target protein that is then degraded by the proteasome [45].…”

“…BRAF and MEK inhibitors continue to be developed (Table 3; Supplementary Table S3) with a huge market potential for these drugs to treat an increasing number of different cancers. With the RAF paradox effects of current RAF inhibitors, the approach to inhibiting BRAF has moved to develop "paradox breakers" and allosteric inhibitors that are not prone to activating ERK1/2 signalling in the same way [13]. The effects of these drugs on the heart are difficult to predict, but as the RAF inhibitors become more effective, with development of pan-RAF inhibitors that avoid the RAF paradox, they may be expected to have the same consequences as MEK Figure 2.…”