Journal
PHARMACOLOGY & THERAPEUTICS
Volume 187, Issue -, Pages 45-60Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2018.02.007
Keywords
BRAF; Cancer; ERK; Inhibitors; MEK; RAS
Categories
Funding
- Astex Pharmaceuticals through the Milner Therapeutics Consortium
- Institute Strategic Programme Grant [BB/P013384/1]
- Worldwide Cancer Research [12-1259]
- Cancer Research UK [A14867]
- AstraZeneca
- Astex Pharmaceuticals
- BBSRC [BBS/E/B/000C0419, BBS/E/B/000C0417, BBS/E/B/000C0433] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0419, BBS/E/B/000C0433, BBS/E/B/000C0417, BBS/E/B/0000C199] Funding Source: researchfish
- Cancer Research UK [14867] Funding Source: researchfish
- Worldwide Cancer Research [12-1259] Funding Source: researchfish
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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, MEKI 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 ERKI/2 for a variety of reasons. First, since the pathway is linear from RAF-to-MEK-to-ERK then ERKI/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. (C) 2018 Published by Elsevier Inc.
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