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

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Article number29
JournalBreast Cancer Research
Volume23
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

Keywords

  • Breast cancer
  • Chemotherapy
  • MDM2 inhibitor
  • MDM4 inhibitor
  • p53

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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