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

doi:10.1186/s13058-021-01406-x

Abstract

BackgroundMDM2/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.MethodsThree 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.ResultsALRN-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.ConclusionThe significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

Highlights

Key functions of the cellular tumor suppressor p53 are to prevent the development of malignancy and stop the growth and expansion of abnormal cells through repair of DNA damage, arresting cell cycle, induction of apoptosis, and controlling angiogenesis [1]
ALRN-6924 inhibits breast cancer cell growth in vitro In order to confirm the anti-cancer activity of ALRN6924 is associated with functional p53, we tested the efficacy of ALRN-6924 in 302 cell lines which represent multiple solid and hematologic cancer types
We found that ALRN-6924 was highly active in 95 cell lines out of 102 cell lines with wild-type TP53 status (WT TP53)

Summary

Introduction

Key functions of the cellular tumor suppressor p53 are to prevent the development of malignancy and stop the growth and expansion of abnormal cells through repair of DNA damage, arresting cell cycle, induction of apoptosis, and controlling angiogenesis [1]. Two different models of biological functions of mouse double minute (MDM) proteins have previously been proposed where in the first model, Mdm and Mdm act independently by regulating specific activities of p53. In this model, it is proposed that p53 levels are mainly being regulated by MDM2, and the transcriptional activity by MDMX. 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

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Results

Discussion

Conclusion