Anaplastic lymphoma kinase activity is essential for the proliferation and survival of anaplastic large-cell lymphoma cells.
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.
Wan
Weihua
W
Oncology, Cephalon Inc, 145 Brandywine Pkwy, West Chester, PA 19380, USA.
Albom
Mark S
MS
Lu
Lihui
L
Quail
Matthew R
MR
Becknell
Nadine C
NC
Weinberg
Linda R
LR
Reddy
Dandu R
DR
Holskin
Beverly P
BP
Angeles
Thelma S
TS
Underiner
Ted L
TL
Meyer
Sheryl L
SL
Hudkins
Robert L
RL
Dorsey
Bruce D
BD
Ator
Mark A
MA
Ruggeri
Bruce A
BA
Cheng
Mangeng
M
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
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