Abstract 1686
Background
Novel therapeutic strategies are needed for the treatment of triple negative breast cancer (TNBC). Inhibition of bromo and extraterminal domains (BET) has shown an anti-proliferative effect in TNBC as well as a synergistic interaction with polo-like kinase (PLK) inhibitors. As for many other therapeutic interventions, resistance to BET inhibitors is expected to occur at a given treatment point.
Methods
We generated two resistant models to the BET inhibitor JQ1, MDA-MB 231R and HS578TR. Western-blot, flow cytometry analysis, genomic and pharmacologic inhibition were executed to evaluate the anti-proliferative activity and biochemical effect. Nude mice were used to explore the in vivo pharmacological efficacy.
Results
We report the generation of two resistant models to the BET inhibitor JQ1. In both models, resistant cells were particularly sensitive to PLK1 inhibition, and reduced cell proliferation in 2D and 3D cell cultures. Although PLK1 levels were similar in sensitive and resistant cell lines, pharmacological inhibition of BRD4 using JQ1 reduced PLK1 to a less extent in the resistant model, effect not observed with BRD4 gene downregulation. PLK1 inhibitor volasertib induced G2/M arrest in both cell lines, and this effect was more evident in resistant cells, in addition to an increase in pH3 and pCDK1. Combination of volasertib and JQ1 induced apoptosis that was partially caspase dependent. A slight activation of Erk1/2 and pS6 was observed in the resistant model, but the inhibition of these kinases did not have a different effect on proliferation compared with the sensitive one. Finally, JQ1-resistant cells xenografted in mice displayed resistance to JQ1 that was reversed after administration of the PLK1 inhibitor volasertib.
Conclusions
PLK1 inhibition reverts resistance to BET inhibitors in our in vivo and in vitro models. These findings open avenues for further drug combinations in the clinical setting.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Universidad de Castilla-La Mancha.
Funding
Instituto de Salud Carlos III; ACEPAIN; CRIS CANCER; Diputación Albacete; UCLM.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5489 - Local immune status in cancer cell nests can be a predictor of survival for rectal cancer with neoadjuvant radiotherapy
Presenter: xijin lin
Session: Poster Display session 2
Resources:
Abstract
1653 - Impact of concomitant medications on disease free survival (DFS) and overall survival (OS) in patients from the PETACC8 study.
Presenter: Clémence Brun
Session: Poster Display session 2
Resources:
Abstract
5206 - Updated results of NORDIC 8, a randomised trial of cetuximab every 2 weeks with FOLFIRI or cetuximab with alternating FOLFIRI/FOLFOX in patients with RAS and BRAF wild type metastatic colorectal cancer.
Presenter: Per Pfeiffer
Session: Poster Display session 2
Resources:
Abstract
2992 - Clinical impact of mucinous and poorly differentiated tumors on the outcome of patients with stage II colon cancer: a TOSCA subgroup analysis
Presenter: Gerardo Rosati
Session: Poster Display session 2
Resources:
Abstract
4753 - Exercise improved adjuvant treatment completion rates and treatment-related toxicities in colorectal cancer: A prospective pilot study
Presenter: Hong Jun Kim
Session: Poster Display session 2
Resources:
Abstract
2735 - Bevacizumab plus Oxaliplatin-Based Chemotherapy as Adjuvant Treatment for Colon Cancer (CC): Updated analysis of stage II disease from the AVANT Phase III Randomized trial by the GERCOR Group
Presenter: Aimery De Gramont
Session: Poster Display session 2
Resources:
Abstract
1843 - Multicenter Validation of the Postoperative Carcinoembryonic Antigen Combined Prognostic Model for Stage Ⅲ Colon Cancer
Presenter: Ji Zhu
Session: Poster Display session 2
Resources:
Abstract
2554 - Impact of the IDEA study on clinical practice for stage III colon cancer patients: a French GERCOR - FFCD - GI UNICANCER national survey.
Presenter: Kaissa Ouali
Session: Poster Display session 2
Resources:
Abstract
3285 - Sex hormones and sperm parameters after adjuvant oxaliplatin-based treatment for colorectal cancer
Presenter: Philip Falk
Session: Poster Display session 2
Resources:
Abstract
3905 - Loss of CDX-2 expression is an independent poor prognostic biomarker in colorectal cancer
Presenter: Krittiya Korphaisarn
Session: Poster Display session 2
Resources:
Abstract