Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer

被引：155

作者：

Merino, Delphine ^{[1
,2
]}

Whittle, James R. ^{[1
,2
,3
]}

Vaillant, Francois ^{[1
,2
]}

Serrano, Antonin ^{[1
,2
]}

Gong, Jia-Nan ^{[2
,4
]}

Giner, Goknur ^{[2
,5
]}

Maragno, Ana Leticia ^{[6
]}

Chanrion, Maia ^{[6
]}

Schneider, Emilie ^{[6
]}

Pal, Bhupinder ^{[1
,2
]}

Li, Xiang ^{[2
,7
]}

Dewson, Grant ^{[2
,7
]}

Grasel, Julius ^{[1
,2
]}

Liu, Kevin ^{[1
,2
]}

Lalaoui, Najoua ^{[2
,7
]}

Segal, David ^{[2
,4
]}

Herold, Marco J. ^{[2
,8
]}

Huang, David C. S. ^{[2
,4
]}

Smyth, Gordon K. ^{[5
,9
]}

Geneste, Olivier ^{[6
]}

Lessene, Guillaume ^{[2
,10
,11
]}

Visvader, Jane E. ^{[1
,2
]}

Lindeman, Geoffrey J. ^{[1
,3
,12
,13
,14
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, ACRF Stem Cells & Canc Div, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[3] Peter MacCallum Canc Ctr, Dept Med Oncol, Melbourne, Vic 3000, Australia

[4] Walter & Eliza Hall Inst Med Res, Canc & Haematol Div, Parkville, Vic 3052, Australia

[5] Walter & Eliza Hall Inst Med Res, Bioinformat Div, Parkville, Vic 3052, Australia

[6] Inst Rech Servier Oncol, R&D Unit, F-78290 Croissy Sur Seine, France

[7] Walter & Eliza Hall Inst Med Res, Cell Signalling & Cell Death Div, Parkville, Vic 3052, Australia

[8] Walter & Eliza Hall Inst Med Res, Mol Genet Canc Div, Parkville, Vic 3052, Australia

[9] Univ Melbourne, Sch Math & Stat, Parkville, Vic 3010, Australia

[10] Walter & Eliza Hall Inst Med Res, Chem Biol Div, Parkville, Vic 3052, Australia

[11] Univ Melbourne, Dept Pharmacol & Therapeut, Parkville, Vic 3010, Australia

[12] Univ Melbourne, Dept Med, Parkville, Vic 3010, Australia

[13] Royal Melbourne Hosp, Parkville Familial Canc Ctr, Parkville, Vic 3050, Australia

[14] Peter MacCallum Canc Ctr, Parkville, Vic 3050, Australia

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2017年 / 9卷 / 401期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

SELECTIVE SMALL-MOLECULE; DIFFERENTIAL EXPRESSION ANALYSIS; TARGETING BCL2; BH3; MIMETICS; IN-VITRO; APOPTOSIS; CELLS; SENSITIVITY; LEUKEMIA; POTENT;

D O I：

10.1126/scitranslmed.aam7049

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The development of BH3 mimetics, which antagonize prosurvival proteins of the BCL-2 family, represents a potential breakthrough in cancer therapy. Targeting the prosurvival member MCL-1 has been an area of intense interest because it is frequently deregulated in cancer. In breast cancer, MCL-1 is often amplified, and high expression predicts poor patient outcome. We tested the MCL-1 inhibitor S63845 in breast cancer cell lines and patient-derived xenografts with high expression of MCL-1. S63845 displayed synergistic activity with docetaxel in triple-negative breast cancer and with trastuzumab or lapatinib in HER2-amplified breast cancer. Using S63845-resistant cells combined with CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated 9) technology, we identified deletion of BAK and up-regulation of prosurvival proteins as potential mechanisms that confer resistance to S63845 in breast cancer. Collectively, our findings provide a strong rationale for the clinical evaluation of MCL-1 inhibitors in breast cancer.

引用

页数：10

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