Targeting ERK, an Achilles' Heel of the MAPK pathway, in cancer therapy

Abstract

The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.

Keywords: Cancer therapy; Drug resistance; ERK inhibitor; ERK kinase; Extracellular signal-regulated kinase; Mitogen-activated protein kinases.

Graphical abstract

Figure 1

The major RAS family numbers. The RAS GTPase superfamily is composed of five main families, RAS, RHO, RAN, RAB and ARF. The Ras family itself is further divided into 6 subfamilies, RAS, RAL, RAP, RAD, RHEB and RIT.

Figure 2

The major downstream targets of ERK1/2 in the MAPK pathway. ERK regulates both cytosolic targets and nuclear transcription factors, thus promoting proliferation, survival and other malignant phenotypes.

Figure 3

Activation and feedback regulation of the MAPK pathway. The classical MAPK pathway is activated in human tumors by upstream receptor tyrosine kinases (RTK) or by mutations in RAS, BRAF, and MEK1. RTKs activate RAS by recruiting adaptor proteins (e.g., GRB-2) and exchange factors (e.g., SOS). RAS activation promotes the formation of RAF dimers, which activate MEK-ERK cascade through phosphorylation. ERK pathway activity is regulated by negative feedback at multiple levels, including the transcriptional activation of DUSP proteins that negatively regulate the pathway. ERK also phosphorylates and thus regulates CRAF and MEK activity directly. ERK, or its immediate substrate RSK, also phosphorylates SOS at several residues, inhibiting its activity and thus negatively regulating RAS activity.

Figure 4

Therapeutic potential in cancers that are resistant to MEK and BRAF inhibitors. Resistance to BRAF inhibitors can occur through various mechanisms, including activating BRAF mutations and BRAF amplification, which can be overcome by both MEK inhibitors (MEKi) and ERK inhibitors (ERKi). ERK inhibitors have the advantage to further overcome resistance to MEK inhibitors that occurs upon MEK mutation.