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
1694 - Pembrolizumab (pembro) Plus mFOLFOX or FOLFIRI in Patients With Metastatic Colorectal Cancer (mCRC): KEYNOTE-651 Cohorts B and D
Presenter: Richard Kim
Session: Poster Display session 2
Resources:
Abstract
908 - Romidepsin (FK228) Regulates the Expression of the Immune Checkpoint Ligand PD-L1 and Exerts Synergistic Anti-Tumor Activity with an Anti-PD-1 Antibody in Colon Cancer
Presenter: Hui Li
Session: Poster Display session 2
Resources:
Abstract
3127 - Prognostic significance of circulating regulatory T lymphocytes (Tregs) in patients with metastatic colorectal cancer (mCRC) under treatment with first line chemotherapy.
Presenter: Zafeiris Zafeiriou
Session: Poster Display session 2
Resources:
Abstract
5416 - The SAFFO study: Sex-related prognostic role And cut-oFf deFinition of monocyte-to-lymphocyte ratio (MLR) in metastatic colOrectal cancer
Presenter: Camilla Lisanti
Session: Poster Display session 2
Resources:
Abstract
2518 - SPICE, a phase I study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: analysis of the metastatic colorectal cancer patients in the dose escalation phase
Presenter: Marwan Fakih
Session: Poster Display session 2
Resources:
Abstract
4000 - Phase 1/2 study with CXCL12 inhibitor NOX-A12 and pembrolizumab in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer
Presenter: Niels Halama
Session: Poster Display session 2
Resources:
Abstract
2223 - Microsatellite Instability Status in Metastatic Colorectal Cancer and Effect of Immune Checkpoint Inhibitors on Survival in MSI-High Metastatic Colorectal Cancer
Presenter: Wataru Okamoto
Session: Poster Display session 2
Resources:
Abstract
2569 - Phase II trial of Trametinib (T) and Panitumumab (Pmab) in RAS/RAF wild type (wt) metastatic colorectal cancer (mCRC)
Presenter: Kanan Alshammari
Session: Poster Display session 2
Resources:
Abstract
5402 - Microsatellite instability and immunogenicity in colorectal cancer – do resident memory Tcells (Trm) play a role in colorectal cancer
Presenter: Wei Toh
Session: Poster Display session 2
Resources:
Abstract
5472 - Early response evaluation and CEA response in patients treated in a Danish randomized study comparing trifluridine/tipiracil (TAS-102) with or without bevazicumab in patients with chemorefractory metastatic colorectal cancer (mCRC)
Presenter: Camilla Qvortrup
Session: Poster Display session 2
Resources:
Abstract