title: Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells.
abstract: 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.
authors.affiliation: Oncology, Cephalon Inc, 145 Brandywine Pkwy, West Chester, PA 19380, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wan
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Lihui
authors.initials: L
authors.lastname: Lu
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Quail
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Becknell
authors.forename: Linda R
authors.initials: LR
authors.lastname: Weinberg
authors.forename: Dandu R
authors.initials: DR
authors.lastname: Reddy
authors.forename: Beverly P
authors.initials: BP
authors.lastname: Holskin
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Ted L
authors.initials: TL
authors.lastname: Underiner
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Meyer
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D017209:Apoptosis; D002227:Carbazoles / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases
chemical_list: C540056:CEP 11988; C540057:CEP 14083; D002227:Carbazoles; D007191:Indazoles; D010671:Phenylurea Compounds; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D020169:Caspases