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
3191 - The efficacy and safety of lenvatinib in patients who did not meet the inclusion criteria of the phase 3 trial (REFLECT trial) and those with BCLC Stage B hepatocellular carcinoma - A nationwide multicenter study in Japan-
Presenter: Azusa Sakamoto
Session: Poster Display session 2
Resources:
Abstract
1529 - Prognostic and predictive value of baseline alpha-fetoprotein (AFP) in patients with advanced hepatocellular carcinoma (HCC) treated with ramucirumab from two phase 3 studies (REACH, REACH-2)
Presenter: Andrew Zhu
Session: Poster Display session 2
Resources:
Abstract
2767 - Effect of second-line cabozantinib on health states for patients with advanced hepatocellular carcinoma (aHCC) after sorafenib: QTWiST analysis from the CELESTIAL study
Presenter: Nicholas Freemantle
Session: Poster Display session 2
Resources:
Abstract
2150 - Alpha-fetoprotein (AFP) response in patients with unresectable hepatocellular carcinoma (HCC) in the phase 3 RESORCE trial
Presenter: Jordi Bruix
Session: Poster Display session 2
Resources:
Abstract
3437 - Phase I/II trial of NBTXR3 activated by SBRT in patients with hepatocellular carcinoma or liver metastasis
Presenter: Marc Pracht
Session: Poster Display session 2
Resources:
Abstract
1758 - Efficacy and safety of ramucirumab (RAM) for advanced hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) following first-line sorafenib across age subgroups in two global phase 3 trials (REACH and REACH-2)
Presenter: Masatoshi Kudo
Session: Poster Display session 2
Resources:
Abstract
1192 - Ramucirumab in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): An exposure–response analysis
Presenter: Josep Llovet
Session: Poster Display session 2
Resources:
Abstract
1600 - Outcomes of Hepatocellular Carcinoma (HCC) Patients Treated with Nivolumab: The Mount Sinai Hospital Experience.
Presenter: Sirish Dharmapuri
Session: Poster Display session 2
Resources:
Abstract
2364 - Pembrolizumab vs Chemotherapy in Patients With Advanced/Metastatic Adenocarcinoma (AC) or Squamous Cell Carcinoma (SCC) of the Esophagus as Second-Line Therapy: Analysis of the Chinese Subgroup in KEYNOTE-181
Presenter: Jia Chen
Session: Poster Display session 2
Resources:
Abstract
1933 - A national comparative effectiveness study to assess definitive chemoradiation regimens in proximal oesophageal squamous cell cancer
Presenter: Judith de Vos-Geelen
Session: Poster Display session 2
Resources:
Abstract