2. Academic Validation
  3. Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer

Inhibition of the mitotic kinase PLK1 overcomes therapeutic resistance to BET inhibitors in triple negative breast cancer

  • Cancer Lett. 2020 Oct 28;491:50-59. doi: 10.1016/j.canlet.2020.06.020.
Cristina Nieto-Jimenez 1,  Eva M Galan-Moya 2,  Veronica Corrales-Sanchez 3,  Maria Del Mar Noblejas-Lopez 1,  Miguel Burgos 3,  Beatriz Domingo 4,  Juan Carlos Montero 5,  Monica Gomez-Juarez 3,  Maria Granada Picazo-Martinez 3,  Azucena Esparis-Ogando 5,  Atanasio Pandiella 5,  Alberto Ocaña 6
Affiliations

Affiliations

  • 1 Translational Research Unit, Albacete University Hospital, Albacete, Spain; Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain.
  • 2 Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain. Electronic address: EvaMaria.Galan@uclm.es.
  • 3 Translational Research Unit, Albacete University Hospital, Albacete, Spain.
  • 4 Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain.
  • 5 Instituto de Biología Molecular y Celular del Cáncer del CSIC, IBSAL and CIBERONC, Salamanca, Spain.
  • 6 Translational Research Unit, Albacete University Hospital, Albacete, Spain; Centro Regional de Investigaciones Biomédicas (CRIB), Universidad de Castilla La Mancha, Albacete, Spain; Hospital Clínico Universitario San Carlos, IDISSC and CIBERONC, Madrid, Spain. Electronic address: alberto.ocana@salud.madrid.org.
PMID: 32735909 DOI: 10.1016/j.canlet.2020.06.020
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.

Keywords

Cancer resistance; Caspase-dependent apoptotic cell death; Epigenetic; JQ1; Volasertib.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z