PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Montaudon, Elodie; Nikitorowicz-Buniak, Joanna; Sourd, Laura; Morisset, Ludivine; Botty, Rania El; Huguet, Léa; Dahmani, Ahmed; Painsec, Pierre; Nemati, Fariba; Vacher, Sophie; Chemlali, Walid; Masliah-Planchon, Julien; Château-Joubert, Sophie; Rega, Camilla; Leal, Mariana Ferreira; Simigdala, Nikiana; Pancholi, Sunil; Ribas, Ricardo; Nicolas, André; Meseure, Didier; Vincent-Salomon, Anne; Reyes, Cécile; Rapinat, Audrey; Gentien, David; Larcher, Thibaut; Bohec, Mylène; Baulande, Sylvain; Bernard, Virginie; Decaudin, Didier; Coussy, Florence; Romancer, Muriel Le; Dutertre, Guillaume; Tariq, Zakia; Cottu, Paul; Driouch, Keltouma; Bièche, Ivan; Martin, Lesley-Ann; Marangoni, Elisabetta

PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Elodie Montaudon, Joanna Nikitorowicz-Buniak, Laura Sourd, Ludivine Morisset, Rania El Botty, Léa Huguet, Ahmed Dahmani, Pierre Painsec, Fariba Nemati, Sophie Vacher, Walid Chemlali, Julien Masliah-Planchon, Sophie Château-Joubert, Camilla Rega, Mariana Ferreira Leal, Nikiana Simigdala, Sunil Pancholi, Ricardo Ribas, André Nicolas, Didier Meseure, Anne Vincent-Salomon, Cécile Reyes, Audrey Rapinat, David Gentien, Thibaut Larcher, Mylène Bohec, Sylvain Baulande, Virginie Bernard, Didier Decaudin, Florence Coussy, Muriel Le Romancer, Guillaume Dutertre, Zakia Tariq, Paul Cottu, Keltouma Driouch, Ivan Bièche, Lesley-Ann Martin and Elisabetta Marangoni ()
Additional contact information
Elodie Montaudon: Translational Research Department, Institut Curie
Joanna Nikitorowicz-Buniak: Institute of Cancer Research
Laura Sourd: Translational Research Department, Institut Curie
Ludivine Morisset: Translational Research Department, Institut Curie
Rania El Botty: Translational Research Department, Institut Curie
Léa Huguet: Translational Research Department, Institut Curie
Ahmed Dahmani: Translational Research Department, Institut Curie
Pierre Painsec: Translational Research Department, Institut Curie
Fariba Nemati: Translational Research Department, Institut Curie
Sophie Vacher: Department of Genetics, Institut Curie
Walid Chemlali: Department of Genetics, Institut Curie
Julien Masliah-Planchon: Department of Genetics, Institut Curie
Sophie Château-Joubert: Alfort Veterinary School
Camilla Rega: Institute of Cancer Research
Mariana Ferreira Leal: Institute of Cancer Research
Nikiana Simigdala: Institute of Cancer Research
Sunil Pancholi: Institute of Cancer Research
Ricardo Ribas: Institute of Cancer Research
André Nicolas: Department of Pathology, Institut Curie
Didier Meseure: Department of Pathology, Institut Curie
Anne Vincent-Salomon: Department of Pathology, Institut Curie
Cécile Reyes: Translational Research Department, Institut Curie
Audrey Rapinat: Translational Research Department, Institut Curie
David Gentien: Translational Research Department, Institut Curie
Thibaut Larcher: INRA, APEX-PAnTher, Oniris
Mylène Bohec: Genomics of Excellence (ICGex) Platform, Institut Curie Research Center
Sylvain Baulande: Genomics of Excellence (ICGex) Platform, Institut Curie Research Center
Virginie Bernard: Department of Genetics, Institut Curie
Didier Decaudin: Translational Research Department, Institut Curie
Florence Coussy: Translational Research Department, Institut Curie
Muriel Le Romancer: Inserm U1052, Centre de Recherche en Cancérologie de Lyon
Guillaume Dutertre: Department of Surgery, Institut Curie
Zakia Tariq: Department of Genetics, Institut Curie
Paul Cottu: Department of Medical Oncology, Institut Curie
Keltouma Driouch: Department of Genetics, Institut Curie
Ivan Bièche: Department of Genetics, Institut Curie
Lesley-Ann Martin: Institute of Cancer Research
Elisabetta Marangoni: Translational Research Department, Institut Curie

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1-driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1-driven BC, including patients progressing on palbociclib treatment.

Date: 2020
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DOI: 10.1038/s41467-020-17697-1

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