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
2104 - Clinical implications of regorafenib-induced hypothyroidism in metastatic colorectal cancer refractory to standard therapies: A prospective evaluation
Presenter: Jwa Hoon Kim
Session: Poster Display session 2
Resources:
Abstract
2143 - Clinical impact of BRAF V600E mutations in patients (pts) with resectable solitary colorectal liver metastases (CRLM)
Presenter: Shin Kobayashi
Session: Poster Display session 2
Resources:
Abstract
3136 - Trifluridine/tipiracil in metastatic colorectal cancer: an updated multicentre real-world analysis on efficacy, safety and predictive factors.
Presenter: Chara Stavraka
Session: Poster Display session 2
Resources:
Abstract
4234 - Correlation between p53 expression and clinical outcome in RAS/BRAF wild type metastatic colorectal cancer patients receiving later-line irinotecan-cetuximab
Presenter: Eleonora Lai
Session: Poster Display session 2
Resources:
Abstract
4287 - Safety and effectiveness of aflibercept + FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC): OZONE secondary analyses
Presenter: Ian Chau
Session: Poster Display session 2
Resources:
Abstract
1820 - A Phase Ib study of the safety and efficacy of atezolizumab (atezo) + bevacizumab (bev) + cobimetinib (cobi) in patients (pts) with metastatic colorectal cancer (mCRC)
Presenter: Johanna Bendell
Session: Poster Display session 2
Resources:
Abstract
5644 - Development and validation of a metastasis-associated immune prognostic model for concurrent metastatic colorectal cancer
Presenter: Zhiwen Luo
Session: Poster Display session 2
Resources:
Abstract
5697 - Prognostic role of blood cell count-based immuno-inflammatory parameters in the Valentino trial
Presenter: Giovanni Fuca
Session: Poster Display session 2
Resources:
Abstract
4704 - Evaluation of safety, immunogenicity and preliminary efficacy of PolyPEPI1018 vaccine in subjects with metastatic colorectal cancer (mCRC) with a predictive biomarker
Presenter: Joleen Hubbard
Session: Poster Display session 2
Resources:
Abstract
3266 - Morphology of tumor-associated macrophages dictates the prognosis of patients with colorectal liver metastases.
Presenter: Matteo Donadon
Session: Poster Display session 2
Resources:
Abstract