文章：

靶向Tyro3、Axl和MerTK受体酪氨酸激酶可显著增强三阴性乳腺癌对CDK4/6抑制的敏感性

Targeting Tyro3, Axl, and MerTK Receptor Tyrosine Kinases Significantly Sensitizes Triple-Negative Breast Cancer to CDK4/6 Inhibition

原文发布日期：18 June 2024

DOI: 10.3390/cancers16122253

类型: Article

开放获取: 是

英文摘要：

Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated byRB1inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not expressRB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.

摘要翻译： 

三阴性乳腺癌（TNBC）是最具侵袭性的亚型，具有高转移率和高死亡率。由于缺乏如ER和HER2等可作用靶点，TNBC的治疗仍面临未满足的临床挑战。尽管TNBC中CDK4/6表达水平较高，但由于耐药性的出现，CDK4/6抑制剂在TNBC中的疗效有限。这种耐药性主要由RB1失活介导。为克服CDK4/6抑制剂耐药，本研究主要采用不表达RB1的细胞系。通过对CDK4/6抑制后激活的受体酪氨酸激酶（RTKs）进行筛选，我们发现TAM（Tyro3、Axl和MerTK）受体酪氨酸激酶是TNBC的关键治疗脆弱点。研究表明，使用新型抑制剂西曲替尼靶向TAM受体能显著增强TNBC对CDK4/6抑制剂的敏感性。经过长期HER2抑制剂治疗后，HER2阳性乳腺癌会抑制HER2表达，在生理上转化为类TNBC细胞。我们进一步证实联合治疗对耐药性HER2阳性乳腺癌同样高效。通过定量蛋白质组学和RNA-seq数据分析，我们将研究延伸至TNBC的免疫表型分析。鉴于TAM受体在促进免疫抑制性肿瘤微环境形成中的作用，我们进一步证明CDK4/6抑制剂阿贝西利与西曲替尼的联合用药能改变TNBC的免疫景观，从而增强免疫检查点阻断疗法的效果。总体而言，本研究为TNBC及潜在治疗耐药性HER2阳性乳腺癌提供了一种新型高效联合治疗方案，该方案具备快速推向临床应用的潜力。

原文链接：

Targeting Tyro3, Axl, and MerTK Receptor Tyrosine Kinases Significantly Sensitizes Triple-Negative Breast Cancer to CDK4/6 Inhibition