title: LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers.
abstract: LIM kinases (LIMK) are emerging targets for cancer therapy, and they function as network hubs to coordinate actin and microtubule dynamics. When LIMKs are inhibited, actin microfilaments are disorganized and microtubules are stabilized. Owing to their stabilizing effect on microtubules, LIMK inhibitors may provide a therapeutic strategy to treat taxane-resistant cancers. In this study, we investigated the effect of LIMK inhibition on breast tumor development and on paclitaxel-resistant tumors, using a novel selective LIMK inhibitor termed Pyr1. Treatment of breast cancer cells, including paclitaxel-resistant cells, blocked their invasion and proliferation in vitro and their growth in vivo in tumor xenograft assays. The tumor-invasive properties of Pyr1 were investigated in vivo by intravital microscopy of tumor xenografts. A striking change of cell morphology was observed with a rounded phenotype arising in a subpopulation of cells, while other cells remained elongated. Notably, although Pyr1 decreased the motility of elongated cells, it increased the motility of rounded cells in the tumor. Pyr1 administration prevented the growth of metastasis but not their spread. Overall, our results provided a preclinical proof of concept concerning how a small-molecule inhibitor of LIMK may offer a strategy to treat taxane-resistant breast tumors and metastases. Cancer Res; 76(12); 3541-52. ©2016 AACR.
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Polarity, Development and Cancer", Université Grenoble Alpes, Grenoble, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Prunier
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Cancer targets and experimental therapeutics", Université Grenoble Alpes, Grenoble, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Josserand
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Cancer targets and experimental therapeutics", Université Grenoble Alpes, Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Vollaire
authors.affiliation: Cancer Genomics Netherlands-Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beerling
authors.affiliation: CNRS ERL5284, INSERM U823, Institut Albert Bonniot, Université Grenoble Alpes, Grenoble, France.
authors.forename: Christos
authors.initials: C
authors.lastname: Petropoulos
authors.affiliation: CNRS ERL5284, INSERM U823, Institut Albert Bonniot, Université Grenoble Alpes, Grenoble, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Destaing
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Polarity, Development and Cancer", Université Grenoble Alpes, Grenoble, France.
authors.forename: Christopher
authors.initials: C
authors.lastname: Montemagno
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Cancer targets and experimental therapeutics", Université Grenoble Alpes, Grenoble, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Hurbin
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Polarity, Development and Cancer", Université Grenoble Alpes, Grenoble, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Prudent
authors.affiliation: Translational Research Department, Institut Curie, Paris, France.
authors.forename: Leanne
authors.initials: L
authors.lastname: de Koning
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
authors.forename: Pascale A
authors.initials: PA
authors.lastname: Cohen
authors.affiliation: CNRS ERL5284, INSERM U823, Institut Albert Bonniot, Université Grenoble Alpes, Grenoble, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Albiges-Rizo
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Cancer targets and experimental therapeutics", Université Grenoble Alpes, Grenoble, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Coll
authors.affiliation: Cancer Genomics Netherlands-Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Jacco
authors.initials: J
authors.lastname: van Rheenen
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Polarity, Development and Cancer", Université Grenoble Alpes, Grenoble, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Billaud
authors.affiliation: INSERM U823, Institut Albert Bonniot, Team "Polarity, Development and Cancer", Université Grenoble Alpes, Grenoble, France. laurence.lafanechere@univ-grenoble-alpes.fr.
authors.forename: Laurence
authors.initials: L
authors.lastname: Lafanechère
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D054461:Lim Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: C000621820:9-benzoyloxy-5,11-dimethyl-2H,6H-pyrido(4,3-b)carbazol-1-one; D002227:Carbazoles; D047428:Protein Kinase Inhibitors; D054461:Lim Kinases