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.
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DOI：
10.1186/s13058-021-01406-x
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发表时间：
2021-03-04
期刊：
影响因子：
--
通讯作者：
Meric-Bernstam F
中科院分区：
文献类型：
--
作者：
Pairawan S;Zhao M;Yuca E;Annis A;Evans K;Sutton D;Carvajal L;Ren JG;Santiago S;Guerlavais V;Akcakanat A;Tapia C;Yang F;Bose PSC;Zheng X;Dumbrava EI;Aivado M;Meric-Bernstam F
在激素受体阳性(ER+)乳腺癌中，MDM2/MDMX蛋白经常升高。我们试图确定MDM2/MDMX的双重抑制剂ALRN-6924联合化疗在ER+乳腺癌模型中的抗肿瘤效果。对代表多种肿瘤类型的302个细胞株进行筛选，以确认TP53状态在ALRN-6924疗效中的作用。采用ER+乳腺癌细胞株(MCF-7和ZR-75-1)，观察ALRN-6924联合用药的抗肿瘤作用。体外细胞增殖、细胞周期和细胞凋亡检测。测定移植瘤体积，用反相蛋白质阵列(RPPA)、免疫组织化学(IHC)和原位末端标记法(TUNEL)观察紫杉醇对ALRN-6924体内药效学的影响。ALRN-6924在野生型TP53(WT-TP53)癌细胞中具有活性，而在突变型TP53中不具有活性。在ER+乳腺癌细胞株上，紫杉醇和茜草素在体外具有协同作用，并能增强体内抗肿瘤活性。流式细胞仪检测显示所有处理组均出现有丝分裂危象，但仅MCF-7单药组和联合用药组的S期细胞减少。RPPA和IHC在体内联合用药组和单用ALRN-6924组均显示p21表达增加。细胞凋亡分析显示，与任何一种药物相比，ALRN-6924与紫杉醇联合治疗组的体内凋亡率显著增加。ALRN-6924与化疗药物联合使用观察到的显著协同作用支持了对激素受体阳性乳腺癌患者的进一步评估。网上版载有补充材料，可在10.1186/s13058-021-01406-x查阅。
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. The online version contains supplementary material available at 10.1186/s13058-021-01406-x.
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影响因子：
9
作者：
Haupt S;Buckley D;Pang JM;Panimaya J;Paul PJ;Gamell C;Takano EA;Lee YY;Hiddingh S;Rogers TM;Teunisse AF;Herold MJ;Marine JC;Fox SB;Jochemsen A;Haupt Y
通讯作者：
Haupt Y
DOI：
10.1158/1078-0432.ccr-16-3133
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kato S;Goodman A;Walavalkar V;Barkauskas DA;Sharabi A;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
3.7
作者：
Mori S;Nada S;Kimura H;Tajima S;Takahashi Y;Kitamura A;Oneyama C;Okada M
通讯作者：
Okada M
DOI：
10.1146/annurev-pathol-012414-040349
发表时间：
2016-05-23
期刊：
Annual review of pathology
影响因子：
--
作者：
Karni-Schmidt O;Lokshin M;Prives C
通讯作者：
Prives C
影响因子：
3.8
作者：
Gonzalez-Angulo AM;Hennessy BT;Meric-Bernstam F;Sahin A;Liu W;Ju Z;Carey MS;Myhre S;Speers C;Deng L;Broaddus R;Lluch A;Aparicio S;Brown P;Pusztai L;Symmans WF;Alsner J;Overgaard J;Borresen-Dale AL;Hortobagyi GN;Coombes KR;Mills GB
通讯作者：
Mills GB