Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer. (28th October 2020)

• Record Type: Journal Article
• Authors: Nieto-Jimenez, Cristina; Galan-Moya, Eva M.; Corrales-Sanchez, Veronica; Noblejas-Lopez, Maria del Mar; Burgos, Miguel; Domingo, Beatriz; Montero, Juan Carlos; Gomez-Juarez, Monica; Picazo-Martinez, Maria Granada; Esparis-Ogando, Azucena; Pandiella, Atanasio; Ocaña, Alberto
• Is Part Of: Cancer letters. Volume 491(2020)
• Page Start: 50
• Page End: 59
• Publication Date: 2020-10-28
• Subjects: Cancer resistance -- Epigenetic -- Volasertib -- JQ1 -- Caspase-dependent apoptotic cell death; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.06.020
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The inhibition of bromo- and extraterminal domains (BET) has shown an anti-proliferative effect in triple negative breast cancer (TNBC). In this article we explore mechanisms of resistance to BET inhibitors (BETi) in TNBC, with the aim of identifying novel ways to overcome such resistance. Two cellular models of acquired resistance to the BET inhibitor JQ1 were generated using a pulsed treatment strategy. MTT, colony formation, and cytometry assays revealed that BETi-resistant cells were particularly sensitive to PLK1 inhibition. Targeting of the latter reduced cell proliferation, especially in resistant cultures. Quantitative PCR analysis of a panel of mitotic kinases uncovered an increased expression of AURKA, TTK, and PLK1, confirmed by Western blot. Only pharmacological inhibition of PLK1 showed anti-proliferative activity on resistant cells, provoking G2/M arrest, increasing expression levels of cyclin B, pH3 and phosphorylation of Bcl-2 proteins, changes that were accompanied by induction of caspase-dependent apoptosis. JQ1-resistant cells orthotopically xenografted into the mammary fat pad of mice led to tumours that retained JQ1-resistance. Administration of the PLK1 inhibitor volasertib resulted in tumour regression. These findings open avenues to explore the future use of PLK1 inhibitors in the clinical setting of BETi-resistant patients. Highlights: BET inhibitors (BETi) are promising therapeutic agents in TNBC for which development of resistance might constitute a mayor limitation. BETi resistant cells display an increased expression of the TNBC-associated kinase PLK1. PLK1 inhibitors (PLK1i) efficiently target BETi resistant cells, decreasing tumour initiation and invasion, leading to apoptotic cell death. Treatment with the PLK1i volasertib induced tumour regression in an in vivo BETi resistant model of xenografted mice. Compounds targeting PLK1 could be explored in TNBC patients with acquired resistant to BETi.