Pairawan Seyed, Zhao Ming, Yuca Erkan, Annis Allen, Evans Kurt, Sutton David, Carvajal Luis, Ren Jian-Guo, Santiago Solimar, Guerlavais Vincent, Akcakanat Argun, Tapia Coya, Yang Fei, Bose Priya Subash Chandra, Zheng Xiaofeng, Dumbrava Ecaterina Ileana, Aivado Manuel, Meric-Bernstam Funda
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Houston, TX, 77030, USA.
Breast Cancer Res. 2021 Mar 4;23(1):29. doi: 10.1186/s13058-021-01406-x.
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.
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.
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.
The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.
MDM2/MDMX蛋白在激素受体阳性（ER+）乳腺癌中常常上调。我们试图确定MDM2/MDMX双重抑制剂ALRN-6924与化疗联合在ER+乳腺癌模型中的抗肿瘤疗效。
对代表多种肿瘤类型的302个细胞系进行筛选，以确认TP53状态在ALRN-6924疗效中的作用。使用ER+乳腺癌细胞系（MCF-7和ZR-75-1）研究ALRN-6924联合用药的抗肿瘤疗效。进行体外细胞增殖、细胞周期和凋亡分析。测量异种移植瘤体积，并对肿瘤组织进行反向蛋白质阵列（RPPA）、免疫组织化学（IHC）和TUNEL分析，以评估ALRN-6924与紫杉醇联合用药的体内药效学作用。
ALRN-6924在野生型TP53（WT-TP53）癌细胞系中具有活性，但在突变型TP53细胞系中无活性。在ER+乳腺癌细胞系中，它在体外具有协同作用，并且与紫杉醇和艾日布林联合使用时体内抗肿瘤活性增强。流式细胞术显示所有治疗组均有有丝分裂危机迹象；然而，仅在MCF-7单药组和ALRN-6924联合用药组中S期减少。RPPA和IHC显示，在体内治疗组中，联合用药组和ALRN-6924单药组的p21表达均增加。凋亡分析显示，与单药组相比，ALRN-6924联合紫杉醇治疗组的体内凋亡率显著提高。
观察到ALRN-6924与化疗药物联合使用具有显著协同作用，这支持在激素受体阳性乳腺癌患者中进行进一步评估。
