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

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

  • Breast Cancer Res. 2021 Mar 4;23(1):29. doi: 10.1186/s13058-021-01406-x.
Seyed Pairawan 1 Ming Zhao 2 Erkan Yuca 2 Allen Annis 3 Kurt Evans 2 David Sutton 3 Luis Carvajal 3 Jian-Guo Ren 3 Solimar Santiago 3 Vincent Guerlavais 3 Argun Akcakanat 2 Coya Tapia 4 5 Fei Yang 4 Priya Subash Chandra Bose 4 Xiaofeng Zheng 6 Ecaterina Ileana Dumbrava 2 Manuel Aivado 3 Funda Meric-Bernstam 7 8 9
Affiliations

Affiliations

  • 1 Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Houston, TX, 77030, USA.
  • 3 Aileron Therapeutics, Cambridge, MA, USA.
  • 4 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Present address: Epizyme Inc., Cambridge, MA, USA.
  • 6 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 7 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Houston, TX, 77030, USA. [email protected]
  • 8 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected]
  • 9 Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected]
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.

Keywords

Breast cancer; Chemotherapy; MDM2 inhibitor; MDM4 inhibitor; p53.

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