PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance.
Elodie MontaudonJoanna Nikitorowicz-BuniakLaura SourdLudivine MorissetRania El BottyLéa HuguetAhmed DahmaniPierre PainsecFariba NematiSophie VacherWalid ChemlaliJulien Masliah-PlanchonSophie Château-JoubertCamilla RegaMariana Ferreira LealNikiana SimigdalaSunil PancholiRicardo RibasAndré NicolasDidier MeseureAnne Vincent-SalomonCécile ReyesAudrey RapinatDavid GentienThibaut LarcherMylène BohecSylvain BaulandeVirginie BernardDidier DecaudinFlorence CoussyMuriel Le RomancerGuillaume DutertreZakia TariqPaul-Henri CottuKeltouma DriouchIvan BiècheLesley-Ann MartinElisabetta MarangoniPublished in: Nature communications (2020)
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.
Keyphrases
- free survival
- gene expression
- cell proliferation
- end stage renal disease
- squamous cell carcinoma
- cell cycle
- estrogen receptor
- endoplasmic reticulum
- metastatic breast cancer
- single cell
- breast cancer cells
- ejection fraction
- small cell lung cancer
- poor prognosis
- peritoneal dialysis
- bone mineral density
- binding protein
- rna seq
- pi k akt
- oxidative stress
- soft tissue
- bone loss
- childhood cancer
- smoking cessation