Targeting the ERK signaling pathway in cancer therapy

Figures & data

Figure 1. Schematic representation of the extracellular signal‐regulated kinase (ERK) pathway focusing on its converging function of diverse intracellular signals. The mitogen‐activated protein (MAP) kinase cascade is composed of three sequential kinases: MAP kinase kinase kinase (MAPKKK), MAP kinase kinase (MAPKK), and MAP kinase (MAPK). ERK1/2 phosphorylate a variety of nuclear, cytosolic and cytoskeletal targets. Integrin‐focal adhesion kinase (FAK) pathway, which is activated by adhesion of integrins to specific extracellular matrix (ECM) molecules, is another important signaling to fully activate the ERK pathway 72,73. Activation of the ERK pathway is most often associated with cell proliferation, cell survival and cell migration. Well‐characterized inhibitors of Raf and MEK1/2 are shown. Several negative regulators of this pathway exist, such as MAP kinase phosphatases (MKPs/DUSPs) and Sprouty proteins. Expression of MKPs and Sprouty proteins is induced in an ERK‐dependent manner, and thus these proteins participate in the negative feedback regulatory loop of the ERK pathway (not shown in this Figure; see text).

Figure 2. Specific inhibitors of the extracellular signal‐regulated kinase (ERK) pathway. Raf inhibitor: BAY 43‐9006. MEK inhibitors: PD98059, U0126, PD184352 (CI‐1040), PD0325901, ARRY‐14886.

Table I. Clinical trials of ERK pathway inhibitors.

Agent	Target (IC50)	Trial phase	Clinical evaluation	Specific comments
BAY 43‐9006	Raf‐1 (6 nM)	II/III	One patient (hepatocellular carcinoma) had a partial response, and 25 patients had stable disease in phase I trial (45 patients). Phase II/III trials are underway in patients with melanoma, renal‐cell, colorectal and hepatocellular carcinomas.	ATP‐competitive; orally active; the major side effects are mild diarrhea and skin rash.
	B‐Raf (22 nM)
	VEGF R‐2 (90 nM)
	VEGF R‐3 (20 nM)
	c‐Kit (68 nM)
	PDGF R‐β (57 nM)
PD184352	MEK1/2 (17 nM)	II	One patient (pancreatic cancer) had a partial response and 19 patients had stable disease in phase I trial (77 patients). No complete or partial responses were observed in phase II trial; 8 patients had stable disease (67 patients).	Non‐ATP‐competitive; orally active; the major side effects are mild diarrhea and skin rash. Clinical trial has been terminated due to its pharmaceutical limitations such as poor solubility, high metabolic clearance and low bioavailability.
PD0325901	MEK1/2 (1 nM)	I/II	Currently underway	Non‐ATP‐competitive; orally active. Prominent anticancer efficacy has been demonstrated for a broad spectrum of human tumor xenografts.
ARRY‐142886	MEK1/2 (12 nM)	I	Currently underway	Non‐ATP‐competitive; orally active. Prominent anticancer efficacy has been demonstrated for a broad spectrum of human tumor xenografts.