Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance.
Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance.
复制标题
建模三阴性乳腺癌的异质性发现了一种新型的组合治疗克服原发性耐药性。
DOI：
10.1002/advs.202003049
复制
发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Maina F
中科院分区：
文献类型：
--
作者：
Lamballe F;Ahmad F;Vinik Y;Castellanet O;Daian F;Müller AK;Köhler UA;Bailly AL;Josselin E;Castellano R;Cayrou C;Charafe-Jauffret E;Mills GB;Géli V;Borg JP;Lev S;Maina F
三阴性乳腺癌（TNBC）是一种高度侵袭性的乳腺癌亚型，其特征在于显著的分子异质性。目前，这种人类疾病还没有有效的药物靶点和先进的临床前模型。在这里，产生了由野生型MET受体表达的微妙增加驱动的乳腺肿瘤的独特小鼠模型（MMTV‐ R26 Met小鼠）。MMTV-R26 Met小鼠发生自发性、排他性TNBC肿瘤，重现了患者对治疗的原发性耐药。MMTV-R26 Met肿瘤的蛋白质组学分析和机器学习方法表明，该模型忠实地再现了人TNBC的肿瘤间异质性。进一步的信号网络分析突出了潜在的药物靶点，其中WEE 1和BCL-XL的共同靶点协同杀死TNBC细胞并有效诱导肿瘤消退。从机制上讲，BCL-XL抑制加剧了TNBC细胞对WEE 1功能的依赖性，导致组蛋白H3和磷酸化S33 RPA 32上调、RRM 2下调、细胞周期扰动、有丝分裂灾难和细胞凋亡。这项研究介绍了一种独特的，强大的小鼠模型，用于研究TNBC的形成和演变，其异质性，并确定有效的治疗靶点。三阴性乳腺癌（TNBC）具有高度侵袭性，目前缺乏有效的治疗方法。本研究报告了产生自发性、排他性TNBC、重现异质性和对治疗的原发性耐药性的独特小鼠模型。其临床相关性通过基于WEE 1和BCL‐XL靶向确定用于TNBC治疗的有效药物组合而进一步加强。
Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets. Triple‐negative breast cancer (TNBC) is highly aggressive and currently lacks effective treatment. This study reports the generation of a unique mouse model developing spontaneous, exclusive TNBC, recapitulating heterogeneity and primary resistance to treatments. Its clinical relevance is further strengthened by the identification of a potent drug combination for TNBC treatment, based on WEE1 and BCL‐XL targeting.
登录
查看更多内容
DOI：
10.1186/bcr1530
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Fantozzi A;Christofori G
通讯作者：
Christofori G
影响因子：
28.2
作者：
Aarts, Marieke;Sharpe, Rachel;Turner, Nicholas C.
通讯作者：
Turner, Nicholas C.
影响因子：
15.9
作者：
Bukhari, Amirali B.;Lewis, Cody W.;Gamper, Armin M.
通讯作者：
Gamper, Armin M.
影响因子：
8
作者：
Greider, C;Chattopadhyay, A;Yang, E
通讯作者：
Yang, E
影响因子：
5.8
作者：
Cassol, Franca;Portal, Loriane;Maina, Flavio
通讯作者：
Maina, Flavio