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
1058 - Assessment of CPS+EG, Neo-Bioscore and modified Neo-Bioscore in breast cancer patients treated with preoperative systemic therapy: a multicenter cohort study
Presenter: LING XU
Session: Poster Display session 2
Resources:
Abstract
1156 - The concordance of treatment decision guided by Oncotype and the PREDICT tool in early stage breast cancer
Presenter: Hadar Goldvaser
Session: Poster Display session 2
Resources:
Abstract
3447 - Influence of first treatment delay on survival among breast cancer subtypes
Presenter: Irene Zarcos Pedrinaci
Session: Poster Display session 2
Resources:
Abstract
3505 - Clinical features of early-stage (I-III) triple-negative breast cancer (TNBC) patients with tumors exhibiting low-overall change in molecular profile after neoadjuvant therapy.
Presenter: Nour Abuhadra
Session: Poster Display session 2
Resources:
Abstract
5442 - Meta-analysis in HER2+ early breast cancer therapies and cost-effectiveness in a Brazilian perspective
Presenter: Marcos Magalhaes
Session: Poster Display session 2
Resources:
Abstract
1570 - Anti-mullerian hormone (AMH) levels and antral follicle counts (AFC) may predict ovarian reserves before systemic chemotherapy (SC) in women with breast cancer(BC); a prospective clinical study
Presenter: Cetin Ordu
Session: Poster Display session 2
Resources:
Abstract
2698 - Prognosis of selected triple negative apocrine breast cancer patients who did not receive adjuvant chemotherapy.
Presenter: Giuseppe Cancello
Session: Poster Display session 2
Resources:
Abstract
3104 - Novel Blood Based Circulating Tumor Cell Biomarker For Breast Cancer Detection
Presenter: Chun-Yu Liu
Session: Poster Display session 2
Resources:
Abstract
4631 - Multi-Gene Prognostic Signatures and Prediction of Pathological Complete Response of ER-Positive HER2-Negative Breast Cancer Patients to Neo-Adjuvant Chemotherapy
Presenter: Claudia Mazo
Session: Poster Display session 2
Resources:
Abstract
4632 - Impact of menopause status on breast cancer outcomes and amenorrhea incidence during adjuvant tailored dose dense chemotherapy
Presenter: Andri Papakonstantinou
Session: Poster Display session 2
Resources:
Abstract