TY - JOUR
T1 - LIM kinase inhibitor Pyr1 reduces the growth and metastatic load of breast cancers
AU - Prunier, Chloé
AU - Josserand, Véronique
AU - Vollaire, Julien
AU - Beerling, Evelyne
AU - Petropoulos, Christos
AU - Destaing, Olivier
AU - Montemagno, Christopher
AU - Hurbin, Amandine
AU - Prudent, Renaud
AU - De Koning, Leanne
AU - Kapur, Reuben
AU - Cohen, Pascale A.
AU - Albiges-Rizo, Corinne
AU - Coll, Jean Luc
AU - Van Rheenen, Jacco
AU - Billaud, Marc
AU - Lafanechère, Laurence
PY - 2016/6/15
Y1 - 2016/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84976869371&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-1864
DO - 10.1158/0008-5472.CAN-15-1864
M3 - Article
C2 - 27216191
AN - SCOPUS:84976869371
SN - 0008-5472
VL - 76
SP - 3541
EP - 3552
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -