Inhibition of polo-like kinase 1 (PLK1) in endocrine-resistant ER+ breast cancer.

Abstract

515 Background: Estrogen receptor (ER)-positive breast cancers initially respond to antiestrogens but eventually become hormone-independent and recur. ER+ breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit estrogen-independent ER transcriptional activity and growth. Mechanisms of endocrine resistance remain to be fully characterized. Methods: A siRNA screen was used to identify kinases required for growth of MCF7/LTED cells. PLK1 RNAi oligonucleotides and the small molecule inhibitor volasertib were tested against ER+ LTED cells. Estrogen independent transcription and target genes were assessed with ER reporter assays and qRT-PCR, respectively. Volasertib and fulvestrant were used in ovariectomized athymic mice bearing MCF7 xenografts. Preclinical findings were correlated with RPPA and RNA-seq data from tumor biopsies of patients with ER+/HER2– breast cancer who received letrozole prior to surgery (NCT00651976). Results: A siRNA kinome screen identified Polo-like kinase 1 (PLK1...