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Blood, 15 February 2006, Vol. 107, No. 4, pp. 1617-1623.
Prepublished online as a Blood First Edition Paper on October 27, 2005; DOI 10.1182/blood-2005-08-3254.
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NEOPLASIA
Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells
Weihua Wan,
Mark S. Albom,
Lihui Lu,
Matthew R. Quail,
Nadine C. Becknell,
Linda R. Weinberg,
Dandu R. Reddy,
Beverly P. Holskin,
Thelma S. Angeles,
Ted L. Underiner,
Sheryl L. Meyer,
Robert L. Hudkins,
Bruce D. Dorsey,
Mark A. Ator,
Bruce A. Ruggeri, and
Mangeng Cheng
From the Oncology, Lead Discovery and Profiling, and Chemistry, Cephalon Inc, West Chester, PA.
The roles of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of anaplastic large-cell lymphoma (ALCL) have been well defined; nevertheless, the notion that ALK is a molecular target for the therapeutic modulation of ALK+ ALCL has not been validated thus far. Select fused pyrrolocarbazole (FP)–derived small molecules with ALK inhibitory activity were used as pharmacologic tools to evaluate whether functional ALK is essential for the proliferation and survival of ALK+ ALCL cells in culture. These compounds inhibited interleukin 3 (IL-3)–independent proliferation of BaF3/NPM-ALK cells in an ALK inhibition-dependent manner and significantly blocked colony formation in agar of mouse embryonic fibroblast (MEF) cells harboring NPM-ALK. Inhibition of NPM-ALK phosphorylation in the ALK+ ALCL-derived cell lines resulted in significant inhibition of cell proliferation and induction of apoptotic-cell death, while having marginal effects on the proliferation and survival of K562, an ALK- leukemia cell line. ALK inhibition resulted in cell-cycle G1 arrest and inactivation of ERK1/2, STAT3, and AKT signaling pathways. Potent and selective ALK inhibitors may have therapeutic application for ALK+ ALCL and possibly other solid and hematologic tumors in which ALK activation is implicated in their pathogenesis.
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