Validation and use of a biomarker for clinical development of the MEK1/2 inhibitor ARRY-142886 (AZD6244)

Doyle, M.; Yeh, Ting‐Chi; Suzy, B.; Morrow, Mark; Lee, P. A.; Hughes, Andrew; Cartlidge, S.; Wallace, E. N. K.; Lyssikatos, Joe; Eckhardt, S. Gail; Winkler, James D.

doi:10.1200/jco.2005.23.16_suppl.3075

Cited by 13 publications

(7 citation statements)

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“…The pharmacologic activity of ARRY-142886 in humans has been shown by the observation of concentration-dependent inhibition of TPAinduced ERK1/2 phosphorylation in PBMCs isolated from cancer patients (19). A MEK inhibitor would presumably be most effective in MEK-driven cancers, which may be identified by the presence of activating mutations in B-Raf, Ras, or growth factor receptors and/or elevated levels of ERK1/2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Yeh

Marsh²,

Bernat³

et al. 2007

Clinical Cancer Research

510

376

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Purpose: The Ras-Raf-mitogen-activated protein kinase kinase (MEK) pathway is overactive in many human cancers and is thus a target for novel therapeutics. We have developed a highly potent and selective inhibitor of MEK1/2. The purpose of these studies has been to show the biological efficacy of ARRY-142886 (AZD6244) in enzymatic, cellular, and animal models. Experimental Design: The ability of ARRY-142886 to inhibit purified MEK1 as well as other kinases was evaluated. Its effects on extracellular signal-regulated kinase (ERK) phosphorylation and proliferation in several cell lines were also determined. Finally, the inhibitor was tested in HT-29 (colorectal) and BxPC3 (pancreatic) xenograft tumor models. Results: The IC 50 of ARRY-142886 was determined to be 14 nmol/L against purified MEK1. This activity is not competitive with ATP, which is consistent with the high specificity of compound for MEK1/2. Basal and epidermal growth factor^induced ERK1/2 phosphorylation was inhibited in several cell lines as well as 12-O-tetradecanoylphorbol-13-acetate^induced ERK1/2 phosphorylation in isolated peripheral blood mononuclear cells.Treatment with ARRY-142886 resulted in the growth inhibition of several cell lines containing B-Raf and Ras mutations but had no effect on a normal fibroblast cell line.When dosed orally, ARRY-142886 was capable of inhibiting both ERK1/ 2 phosphorylation and growth of HT-29 xenograft tumors in nude mice. Tumor regressions were also seen in a BxPC3 xenograft model. In addition, tumors remained responsive to growth inhibition after a 7-day dosing holiday. Conclusions: ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies.Excessive growth factor signaling leads to unregulated growth that can contribute to the pathogenesis of human cancer. The signaling cascade is initiated by the binding of peptide growth factors to their tyrosine kinase receptors at the plasma membrane. The receptor kinases are activated and through the recruitment of the growth factor receptor binding protein 2/son of sevenless complex to autophosphorylated sites on the receptors, the G protein Ras is induced to its active GTP-bound state. Ras recruits the serine/threonine kinase Raf to the plasma membrane, where it is then able to phosphorylate and activate mitogen-activated protein kinase kinases (MEK) 1 and 2, which are dual specificity protein kinases that phosphorylate serine/ threonine and tyrosine residues. The MEK kinases in turn phosphorylate and activate their only currently known substrates, extracellular signal-regulated kinases (ERK) 1 and 2. ERK1/2 proteins translocate to the nucleus where they phosphorylate and activate effector proteins and transcription factors, resulting in diverse cellular responses, including proliferation.The overexpression and/or mutation of epidermal growth factor (EGF) receptor (EGFR), erbB2, platelet-derived growth factor receptor, RET, and othe...

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Section: Discussionmentioning

confidence: 99%

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Yeh

Marsh²,

Bernat³

et al. 2007

Clinical Cancer Research

510

376

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“…Two small-molecule MEK inhibitors are currently being evaluated in the clinic, PD-0325901 (5, Pfizer) [54][55][56] and ARRY-142886 (6, AZD-6244, Array and AstraZeneca) [57,58]. These two agents, which are orally bioavailable, are both non-ATP competitive allosteric inhibitors of MEK.…”

Section: The Erk Pathway As a Target For Cancer Drug Discoverymentioning

confidence: 99%

“…• small molecule inhibitors of RAF (BAY 43-9006 (1)) [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. • small molecule inhibitors of MEK (PD-0325901 (5) and ARRY-142886 (6)) [54][55][56][57][58].…”

Section: The Erk Pathway As a Target For Cancer Drug Discoverymentioning

confidence: 99%

Recent Advances in the Research and Development of RAF Kinase Inhibitors

Smith¹,

Dumas²,

Adnane³

et al. 2006

CTMC

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The RAS-RAF-MEK-ERK signaling pathway (ERK pathway) plays a key role in tumorigenesis and cancer progression. Mutations of RAS or B-RAF lead to a constitutive activation of the ERK pathway, which ultimately results in increased cell division, and cell survival. This review article focuses on the recent literature related to ERK pathway inhibitors, with a particular emphasis on RAF kinase inhibitors. Preclinical and clinical data for the RAF kinase inhibitor sorafenib (BAY 43-9006 tosylate), that was recently approved in the US for the treatment of advanced renal cell carcinoma, are also outlined.

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“…Because it is clear that mutations of upstream genes (KRAS, BRAF) are not sufficient for selecting metastatic CRC patients who will benefit from MEK inhibition, predictive biomarker development is actively being pursued [37,39,40]. Nonetheless, clinical development in CRC is proceeding in the KRAS/BRAF-mutated population.…”

Section: Mek Inhibitorsmentioning

confidence: 98%

Management Strategies for Patients with KRAS Mutations

Leong

Eckhardt

Messersmith

2010

Curr Colorectal Cancer Rep

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In an era of targeted therapies and personalized medicine, the search for predictive and prognostic biomarkers has reached the forefront in cancer research. Testing for KRAS mutation status in the treatment of colorectal cancer (CRC) has now become standard of care, especially for patients being considered for treatment with antibodies to the epidermal growth factor receptor (EGFR). Because metastatic CRC patients whose tumors harbor KRAS mutations do not respond to EGFR-targeting antibodies, their management is challenging. As our understanding of the role of KRAS mutations grows, new treatment strategies are being devised but are not yet ready for clinical use. In this review, we examine some of these potential strategies.

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Validation and use of a biomarker for clinical development of the MEK1/2 inhibitor ARRY-142886 (AZD6244)

Cited by 13 publications

References 0 publications

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

Recent Advances in the Research and Development of RAF Kinase Inhibitors

Management Strategies for Patients with KRAS Mutations

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