Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8536800 | Pharmacology & Therapeutics | 2018 | 68 Pages |
Abstract
The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is de-regulated in a variety of cancers due to mutations in receptor tyrosine kinases (RTKs), negative regulators of RAS (such as NF1) and core pathway components themselves (RAS, BRAF, CRAF, MEK1 or MEK2). This has driven the development of a variety of pharmaceutical agents to inhibit RAF-MEK1/2-ERK1/2 signalling in cancer and both RAF and MEK inhibitors are now approved and used in the clinic. There is now much interest in targeting at the level of ERK1/2 for a variety of reasons. First, since the pathway is linear from RAF-to-MEK-to-ERK then ERK1/2 are validated as targets per se. Second, innate resistance to RAF or MEK inhibitors involves relief of negative feedback and pathway re-activation with all signalling going through ERK1/2, validating the use of ERK inhibitors with RAF or MEK inhibitors as an up-front combination. Third, long-term acquired resistance to RAF or MEK inhibitors involves a variety of mechanisms (KRAS or BRAF amplification, MEK mutation, etc.) which re-instate ERK activity, validating the use of ERK inhibitors to forestall acquired resistance to RAF or MEK inhibitors. The first potent highly selective ERK1/2 inhibitors have now been developed and are entering clinical trials. They have one of three discrete mechanisms of action - catalytic, “dual mechanism” or covalent - which could have profound consequences for how cells respond and adapt. In this review we describe the validation of ERK1/2 as anti-cancer drug targets, consider the mechanism of action of new ERK1/2 inhibitors and how this may impact on their efficacy, anticipate factors that will determine how tumour cells respond and adapt to ERK1/2 inhibitors and consider ERK1/2 inhibitor drug combinations.
Keywords
VEGFRAP-1NF1Bcl2Bcl-xLSOSPKBASK1MAP kinase kinaseMTDMOAFRSBRAFHRASEGFRRTKMKPELK1B-cell lymphoma extra largeCCAAT/enhancer-binding protein betaPROTACE2FCRAFRSKMST2E26 transformation-specificMAPK or ERK kinaseE2 transcription factorCDKSARNRASKRASTCOMBPDRSIC50PPImTORHER2ERKEGFRASETsPI3KBtkC/EBP-βDUSPGTPase Activating ProteinMAP kinase phosphataseMAPKMKKMcl1AktSproutyArafProtein-protein interactionBruton's tyrosine kinaseMaximum tolerated dosePAINSdual-specificity phosphataseStructure-activity relationshipRALretinoblastomaCancerGAPepidermal growth factorconcentration causing 50% inhibitionphosphoinositide 3-kinaseB-cell lymphoma 2MEKInhibitorsMechanism of actionMechanistic target of rapamycinribosomal protein S6 kinaseactivator protein 1Myelin basic proteinprotein kinase Bmitogen-activated protein kinaseson-of-sevenlessCatalogue of Somatic Mutations in CancerLigand efficiencyCOSMICSpryextracellular signal-regulated kinaseapoptosis signal-regulating kinase 1cyclin-dependent kinaseReceptor Tyrosine KinaseHuman epidermal growth factor receptor 2vascular endothelial growth factor receptorEpidermal growth factor receptor
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Authors
Andrew M. Kidger, James Sipthorp, Simon J. Cook,