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Breast Cancer Research
Published in: Breast Cancer Research 1/2021

01-12-2021 | Breast Cancer | Research article

First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models

Authors: Seyed Pairawan, Ming Zhao, Erkan Yuca, Allen Annis, Kurt Evans, David Sutton, Luis Carvajal, Jian-Guo Ren, Solimar Santiago, Vincent Guerlavais, Argun Akcakanat, Coya Tapia, Fei Yang, Priya Subash Chandra Bose, Xiaofeng Zheng, Ecaterina Ileana Dumbrava, Manuel Aivado, Funda Meric-Bernstam

Published in: Breast Cancer Research | Issue 1/2021

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Abstract

Background

MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models.

Methods

Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel.

Results

ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent.

Conclusion

The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
Appendix
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Metadata
Title
First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models
Authors
Seyed Pairawan
Ming Zhao
Erkan Yuca
Allen Annis
Kurt Evans
David Sutton
Luis Carvajal
Jian-Guo Ren
Solimar Santiago
Vincent Guerlavais
Argun Akcakanat
Coya Tapia
Fei Yang
Priya Subash Chandra Bose
Xiaofeng Zheng
Ecaterina Ileana Dumbrava
Manuel Aivado
Funda Meric-Bernstam
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2021
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-021-01406-x

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