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

doi:10.1158/0008-5472.CAN-15-1864

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

27 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3541-52
Number of pages	12
Journal	Cancer Research
Volume	76
Issue number	12
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-1864
Publication status	Published - 15 Jun 2016

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Prunier, C., Josserand, V., Vollaire, J., Beerling, E., Petropoulos, C., Destaing, O., Montemagno, C., Hurbin, A., Prudent, R., de Koning, L., Kapur, R., Cohen, P. A., Albiges-Rizo, C., Coll, J.-L., van Rheenen, J., Billaud, M., & Lafanechère, L. (2016). LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers. Cancer Research, 76(12), 3541-52. https://doi.org/10.1158/0008-5472.CAN-15-1864

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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. {\textcopyright}2016 AACR.",

author = "Chlo{\'e} Prunier and V{\'e}ronique Josserand and Julien Vollaire and Evelyne Beerling and Christos Petropoulos and Olivier Destaing and Christopher Montemagno and Amandine Hurbin and Renaud Prudent and {de Koning}, Leanne and Reuben Kapur and Cohen, {Pascale A} and Corinne Albiges-Rizo and Jean-Luc Coll and {van Rheenen}, Jacco and Marc Billaud and Laurence Lafanech{\`e}re",

note = "{\textcopyright}2016 American Association for Cancer Research.",

year = "2016",

month = jun,

day = "15",

doi = "10.1158/0008-5472.CAN-15-1864",

language = "English",

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Prunier, C, Josserand, V, Vollaire, J, Beerling, E, Petropoulos, C, Destaing, O, Montemagno, C, Hurbin, A, Prudent, R, de Koning, L, Kapur, R, Cohen, PA, Albiges-Rizo, C, Coll, J-L, van Rheenen, J, Billaud, M & Lafanechère, L 2016, 'LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers', Cancer Research, vol. 76, no. 12, pp. 3541-52. https://doi.org/10.1158/0008-5472.CAN-15-1864

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. Cancer Res; 76(12); 3541-52. ©2016 AACR.

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. Cancer Res; 76(12); 3541-52. ©2016 AACR.

U2 - 10.1158/0008-5472.CAN-15-1864

DO - 10.1158/0008-5472.CAN-15-1864

M3 - Article

C2 - 27216191

SN - 0008-5472

VL - 76

SP - 3541

EP - 3552

JO - Cancer Research

JF - Cancer Research

IS - 12

ER -

LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers

Abstract

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