Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.

IF 12.5 1区 医学 Q1 ONCOLOGY
Katrina M Piemonte, Natasha N Ingles, Kristen L Weber-Bonk, Mitchell J Valentine, Parth R Majmudar, Salendra Singh, Ruth A Keri
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引用次数: 0

Abstract

Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit antitumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple-negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multipolar spindles, and chromosomal instability. Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated chromosomal instability for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of patients with TNBC treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy.  Significance: YES1 is a sentinel regulator of genomic maintenance that controls centrosome homeostasis and chromosome stability through FOXM1, revealing this pathway as a therapeutic vulnerability for enhancing taxane efficacy in triple-negative breast cancer.

靶向 YES1 可破坏有丝分裂的保真度并增强三阴性乳腺癌对紫杉类药物的反应。
对广谱 Src 家族激酶(SFK)抑制剂进行的临床试验显示,这些抑制剂具有明显的剂量限制毒性,阻碍了实体瘤研究的进展。SFK在功能上具有异质性,因此靶向单个成员是一种既能获得抗肿瘤疗效又能避免毒性的潜在策略。在这里,我们发现YES1是三阴性乳腺癌(TNBC)中最高度过表达的SFK,并且与患者的不良预后有关。通过基因或药理学方法破坏 YES1 可诱导异常有丝分裂、中心体扩增、多极纺锤体和染色体不稳定性(CIN)。从机理上讲,YES1 可维持 FOXM1 蛋白水平,并提高 FOXM1 靶基因的表达,而 FOXM1 靶基因可控制中心体功能,对有效和准确的有丝分裂进程至关重要。在体外和体内 TNBC 模型中,YES1 的抑制增强了紫杉类药物的疗效,紫杉类药物是治疗 TNBC 的基础药物,其疗效需要 CIN 升高。在临床上,YES1表达的升高与接受紫杉类药物和蒽环类药物联合治疗的TNBC患者总生存期的缩短有关。总之,这项研究表明,YES1 是 TNBC 基因组稳定性的重要调节因子,可用于提高紫杉类药物的疗效。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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