MZ1 co-operates with trastuzumab in HER2 positive breast cancer

Abstract

Background Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context, novel drug combinations are needed to increase its antitumor activity. In this work, we have evaluated the efficacy of proteolysis targeting chimera (PROTAC) compounds based on BET inhibitors (BETi) to augment the activity of trastuzumab in HER2+ breast cancer models. Methods BT474 and SKBR3 HER2+ breast cancer cell lines were used. The effects of trastuzumab and the BET-PROTAC MZ1 either alone or in combination, were evaluated using MTT proliferation assays, three-dimensional invasion and adhesion cultures, flow cytometry, qPCR and Western blot. In vivo studies were carried out in a xenografted model in mice. Finally, a Clariom_S_Human transcriptomic array was applied to identify deregulated genes after treatments. Results MZ1 induced a higher antiproliferative effect compared to the BETi JQ1. The combination of MZ1 and -trastuzumab significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone. Evaluation of apoptosis resulted in an increase of cell death following treatment with the combination, and biochemical studies displayed modifications of apoptosis and DNA damage components. In vivo administration of agents alone or combined, to tumors orthotopically xenografted in mice, resulted in a decrease of the tumor volume only after MZ1-Trastuzumab combination treatment. Results from a transcriptomic array indicated a series of newly described transcription factors including HOXB7, MEIS2, TCERG1, and DNAJC2, that were associated to poor outcome in HER2+ breast cancer subtype and downregulated by the MZ1-trastuzumab combination. Conclusions We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development.

Preclinical and Basic Research Strategies for Overcoming Resistance to Targeted Therapies in HER2-Positive Breast Cancer

“…Subsequently, the potential synergistic action between trastuzumab and the BETi MZ1 was explored. As a result, MZ1 was found to augment the anti-proliferative capacity of trastuzumab by DNA damage and inducing apoptosis [137]. Meanwhile, tumor volume decreased significantly after MZ1-Trastuzumab combination treatment in vivo.…”

PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities

“…In Human epidermal growth factor receptor 2 (HER2) positive cells, the combined use of MZ1 and trastuzumab could enhance the induction of apoptosis, leading to better inhibition of tumors. On this basis, nanoparticles conjugated with trastuzumab were used to encapsulate mez1 and deliver it to HER2-positive breast cancer cells, resulting in the increased induction of cancer cells [ 54 , 55 ].…”

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

“…At present, antibody PROTACs are mainly divided into antibody–PROTAC conjugates, AbTACs and GlueTAC ( Fig. 3 A) 140 , 141 , 142 , 143 , 144 , 145 , 146 . Antibody–PROTAC conjugates are a trifunctional macromolecule, which is formed by connecting small molecule PROTAC and specific antibody through a cleavable linker.…”