title: Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC-ALK-positive human diffuse large B cell lymphomas.
abstract: ALK positive diffuse large B-cell lymphomas (DLBCL) are a distinct lymphoma subtype associated with a poor outcome. Most of them feature a t(2;17) encoding a clathrin (CLTC)-ALK fusion protein. The contribution of deregulated ALK-activity in the pathogenesis and maintenance of these DLBCLs is not yet known. We established and characterized the first CLTC-ALK positive DLBCL cell line (LM1). LM1 formed tumors in NOD-SCID mice. The selective ALK inhibitor NVP-TAE684 inhibited growth of LM1 cells in vitro at nanomolar concentrations. NVP-TAE684 repressed ALK-activated signalling pathways and induced apoptosis of LM1 DLBCL cells. Inhibition of ALK-activity resulted in sustained tumor regression in the xenotransplant tumor model. These data indicate a role of CLTC-ALK in the maintenance of the malignant phenotype thereby providing a rationale therapeutic target for these otherwise refractory tumors.
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, Cornell University, New York, New York, United States of America. lec2010@med.cornell.edu
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.forename: Christine
authors.initials: C
authors.lastname: Damm-Welk
authors.forename: Inga
authors.initials: I
authors.lastname: Vater
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Lana
authors.initials: L
authors.lastname: Harder
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.forename: Alfred
authors.initials: A
authors.lastname: Reiter
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Willi
authors.initials: W
authors.lastname: Woessmann
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D016867:Immunocompromised Host; D016130:Immunophenotyping; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012074:Remission Induction; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C516714:NVP-TAE684; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C408996:oncoprotein CLTCL-ALK; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases