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
3082 - Prognostic and predictive role of body mass index (BMI) in metastatic colorectal cancer (mCRC): a pooled analisys of TRIBE and TRIBE-2 studies by GONO
Presenter: Emanuela Dell'Aquila
Session: Poster Display session 2
Resources:
Abstract
3618 - Drug holidays and overall survival in patients treated for metastatic colorectal cancer
Presenter: Silvio Ken Garattini
Session: Poster Display session 2
Resources:
Abstract
6111 - Quality of life during 1st-line FOLFOXIRI+/- panitumumab in RAS wild-type metastatic colorectal cancer: Results from the randomized VOLFI trial (AIO KRK-0109)
Presenter: Michael Geissler
Session: Poster Display session 2
Resources:
Abstract
1042 - A biomarker combination indicating resistance to FOLFOX plus bevacizumab in metastastic colorectal cancer : results of phase I of the PERMAD trial
Presenter: Thomas Seufferlein
Session: Poster Display session 2
Resources:
Abstract
3291 - Microsatellite Instability (MSI) status and prognosis in colorectal cancer: meta-analysis
Presenter: James Toh
Session: Poster Display session 2
Resources:
Abstract
2046 - Choosing the right strategy based on individualized treatment effect predictions: Combination versus sequential chemotherapy in patients with metastatic colorectal cancer.
Presenter: Miriam Koopman
Session: Poster Display session 2
Resources:
Abstract
2589 - Noninferiority on overall survival of every-2-weeks vs weekly schedule of cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer
Presenter: Stefan Kasper
Session: Poster Display session 2
Resources:
Abstract
4944 - POLAF study: Efficacy and safety of FOLFIRI/aflibercept in a phase II trial in patients with metastatic colorectal cancer: Results of plasmatic prognostic and predictive markers
Presenter: Maria Elena Elez Fernandez
Session: Poster Display session 2
Resources:
Abstract
2042 - The accuracy of the clinical PCI score in patients with peritoneal carcinomatosis of colorectal cancer
Presenter: Nadine De Boer
Session: Poster Display session 2
Resources:
Abstract
2667 - The impact of late-line treatment on overall survival (OS) from the initiation of first-line chemotherapy (CT) for patients (pts) with metastatic colorectal cancer (mCRC).
Presenter: Takeshi Kawakami
Session: Poster Display session 2
Resources:
Abstract