LIM kinase inhibitor Pyr1 reduces the growth and metastatic load of breast cancers

Chloé Prunier, Véronique Josserand, Julien Vollaire, Evelyne Beerling, Christos Petropoulos, Olivier Destaing, Christopher Montemagno, Amandine Hurbin, Renaud Prudent, Leanne De Koning, Reuben Kapur, Pascale A. Cohen, Corinne Albiges-Rizo, Jean Luc Coll, Jacco Van Rheenen, Marc Billaud, Laurence Lafanechère

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3541-3552
Number of pages12
JournalCancer Research
Volume76
Issue number12
DOIs
StatePublished - Jun 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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