This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Christensen, J. G. Articles by Los, G. Search for Related Content PubMed PubMed Citation Articles by Christensen, J. G. Articles by Los, G.

Research Articles: Therapeutics, Targets, and Development

Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma

Departments of ¹ Cancer Biology, ² Pharmacokinetics, Dynamics, and Metabolism; ³ Biochemical Pharmacology; and ⁴ Molecular Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, California

Requests for reprints: James G. Christensen, Department of Cancer Research, Pfizer Global Research and Development, La Jolla Laboratories, 10724 Science Center Drive, La Jolla, CA 92121. Phone: 858-638-6336; Fax: 858-526-4120. E-mail: james.christensen{at}pfizer.com

Abstract

A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL). PF-2341066 was recently identified as a p.o. bioavailable, small-molecule inhibitor of the catalytic activity of c-Met kinase and the NPM-ALK fusion protein. PF-2341066 also potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC₅₀ value, 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of >120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G₁-S–phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells (IC₅₀ values, 30 nmol/L) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase–mediated nick-end labeling and Annexin V staining (IC₅₀ values, 25–50 nmol/L). P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 were observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function. Collectively, these data illustrate the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL. [Mol Cancer Ther 2007;6(12):3314–22]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 5/30/07; revised 8/29/07; accepted 10/19/07.

This article has been cited by other articles:

				J. P. Koivunen, C. Mermel, K. Zejnullahu, C. Murphy, E. Lifshits, A. J. Holmes, H. G. Choi, J. Kim, D. Chiang, R. Thomas, et al. EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer Clin. Cancer Res., July 1, 2008; 14(13): 4275 - 4283. [Abstract] [Full Text] [PDF]

				R. Salgia c-Met Receptor Tyrosine Kinase as a Therapeutic Target in Cancer ASCO Educational Book, January 1, 2008; 2008(1): 113 - 118. [Abstract] [Full Text] [PDF]