ERK1/2 inhibitors: New weapons to inhibit the RAS-regulated RAF-MEK1/2-ERK1/2 pathway

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.

Targeting ERK beyond the boundaries of the kinase active site in melanoma

“…ERK phosphorylates numerous substrates in the cytoplasm and nucleus that play a role in cell fate, such as RSK and the AP‐1 and ETS families of transcription factors. (B) The ERK pathway has many intrinsic mechanisms of negative feedback regulation . ERK can exert negative feedback at each level of the pathway via phosphoregulation.…”

“…ERK can exert negative feedback at each level of the pathway via phosphoregulation. ERK can also drive transcription of negative pathway regulators such as DUSP5/6 and SPRY that can and inactivate members of the ERK pathway . Abbreviations: AP‐1, activating protein‐1; ERK, extracellular signal‐regulated kinase; DUSP, dual specificity phosphatase; Grb, growth factor receptor‐bound protein; MEK, mitogen‐activated protein kinase/ERK kinase; RSK, ribosomal s6 kinase; RTK, receptor tyrosine kinase; SOS, Son of Sevenless homolog; SPRY, sprouty homolog [Color figure can be viewed at wileyonlinelibrary.com]…”

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

“…While the quest for direct inhibitors of oncogenic mutated KRAS has been challenging and largely unsuccessful so far, several endeavors tried to pharmacologically inhibit KRAS downstream effector signaling axes instead, either in the form of a single agent or, potentially therapeutically more potent albeit at the same time more prone to adverse toxicity, as combination regimens [1,37,38,39,40]. For example, preclinical studies including work on oncogenic KRAS -driven genetically engineered mouse models hint at a prominent role of epidermal growth factor receptor (EGFR) signaling for pancreatic carcinogenesis and cancer progression [41,42].…”

Anti‐angiogenic effects of the blue‐green alga Arthrospira platensis on pancreatic cancer

“…We recently reported the potent suppressive effects of A platensis on the growth and proliferation of experimental pancreatic cancer . The RAS‐regulated RAF‐MEK1/2‐ERK1/2 pathway, with possible impacts on angiogenesis in the cancer tissue, is dysfunctional in pancreatic cancer . In fact, anti‐angiogenic therapeutic approach targeting the vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) signalling has become a promising strategy in the treatment of pancreatic cancer with the aim to modulate protein kinase B (AKT) and extracellular signal‐regulated kinase (ERK) (pAKT and p‐ERK) pathways dysregulated in these cancers …”

“…4 The RAS-regulated RAF-MEK1/2-ERK1/2 pathway, with possible impacts on angiogenesis in the cancer tissue, 12,13 is dysfunctional in pancreatic cancer. 14,15 In fact, anti-angiogenic therapeutic approach targeting the vascular endothelial growth factor (VEGF) or the epidermal growth factor receptor (EGFR) signalling has become a promising strategy in the treatment of pancreatic cancer 16,17 with the aim to modulate protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) (pAKT and p-ERK) pathways dysregulated in these cancers. 18 Thus, the aim of this current study was to evaluate the possible anti-angiogenic effects of A platensis to account for the antiproliferative effects of this alga.…”