Abstract 1674
Background
Triple negative breast cancer (TNBC) is an incurable disease, therefore novel therapies are needed. Bromo and extraterminal domain inhibitors (BETi) are currently in clinical development with promising activity in TNBC. However, resistance to these agents will limit their efficacy. Proteolysis targeting chimeric (PROTAC) are novel compounds that by binding to a ubiquitin ligase promotes protein degradation.
Methods
In our study we explore the antitumoral activity of two BET-PROTACs, MZ1 and ARV-825 in TNBC and ovarian cancer. We used MDAMB-231, BT549 and MDAMB-231 JQ1 resistant TNBC cells lines; and OVCAR3 and SKOV3 ovarian cancer cells lines. We evaluated the antiproliferation effect using MTT assay, colony-forming assay and three-dimensional cultures in Matrigel. To explore the molecular mechanism of drugs we used flow cytometry (cell cycle and cell death). The analysis of protein expression was determined by western blot. In vivo studies included BALB/c nu/nu mice that were injected with MDAMB-231 JQ1 resistant cells and later treated with BETi JQ1 and BET-PROTAC MZ1.
Results
Both PROTACs efficiently and maintained deleted the levels of BRD4 in MDA-MB-231 and in the resistant JQ1 cell line MDA-MB-231R. MZ1 and ARV-825 showed a profound antiproliferative effect in MDA-MD-231 sensitive and resistant cells using 2D and 3D cultures, and had a similar activity in other triple negative (BT549) and ovarian cancer (SKOV3, OVCAR) cell lines. MZ1 slightly arrested cells at G2/M in sensitive and resistant JQ1 MDA-MB-231 cells. In addition, a profound effect on apoptosis was observed, that was more evident in the sensitive cell line, effect that was caspase dependent. Given the potent antiproliferative activity of MZ1 no synergistic activity was observed when combined with docetaxel, cisplation or olaparib. Finally, administration of MZ1 was able to recue tumor growth in nude mice of MDA-MB-231 JQ1 resistant cells, by reducing the expression of BRD4.
Conclusions
We describe the profound activity of BET-PROTACs in TNBC cell lines and in an in vivo BETi resistant model. This data provides options for further clinical development of these agents in TNBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Instituto de Salud Carlos III (PI16/01121), ACEPAIN; Diputación de Albacete, CIBERONC, CRIS Cancer Foundation, implementation research program of the UCLM System of Science, Technology and Innovation-Secti (co-funded by the European Commission/FSE funds) and scientific foundation of the AECC.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
2107 - Role of Individualized Intervention(s) on Quality of Life (QOL) and Adherence to Adjuvant Endocrine Therapy in Premenopausal Women with Early-Stage Breast Cancer (BC): MyChoice Study
Presenter: Shahid Ahmed
Session: Poster Display session 2
Resources:
Abstract
5812 - Correlation between the density of tumor-infiltrating lymphocytes, immune cell subsets in tumor stroma and response to systemic therapy in breast cancer
Presenter: Cvetka Grasic Kuhar
Session: Poster Display session 2
Resources:
Abstract
4734 - BRCA1/2 Testing in HER2- Advanced Breast Cancer (ABC): Results from the European Component of a Multi-Country Real World Study
Presenter: Michael Patrick Lux
Session: Poster Display session 2
Resources:
Abstract
1686 - In vitro and in vivo rescue of resistance to BET inhibitors by targeting PLK1 in triple negative breast cancer.
Presenter: Cristina Nieto-jiménez
Session: Poster Display session 2
Resources:
Abstract
5020 - Neoadjuvant endocrine therapy in combination with melatonin and metformin in locally advanced breast cancer
Presenter: Tatiana Semiglazova
Session: Poster Display session 2
Resources:
Abstract
5082 - Melatonin and metformin in neoadjuvant chemotherapy in locally advanced breast cancer
Presenter: Tatiana Semiglazova
Session: Poster Display session 2
Resources:
Abstract
2642 - Patient-tailored tamoxifen dosing based on an increased quantitative understanding of its complex pharmacokinetics: A novel integrative modelling approach
Presenter: Anna Mueller-Schoell
Session: Poster Display session 2
Resources:
Abstract
2461 - Lack of benefit of neoadjuvant pertuzumab in high risk HER2 positive breast cancer. A retrospective case-control study of 355 cases with biomarker analysis.
Presenter: Manuela Tiako Meyo
Session: Poster Display session 2
Resources:
Abstract
4776 - Targeting CDCA3 to improve chemotherapy response in triple-negative breast cancer patients
Presenter: Kenneth O'Byrne
Session: Poster Display session 2
Resources:
Abstract
5629 - Outcome of triple negative inflammatory breast cancers (TNIBC) treated with dose dense neoadjuvant epirubicin cyclophosphmide, prognostic impact of pre and post neoadjuvant chemotherapy (NAC) tumor infiltrating lymphocytes (TIL) and post NAC lymphovascular invasion
Presenter: Luca Campedel
Session: Poster Display session 2
Resources:
Abstract