PDF(Pubmed)
Abstract：
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 by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. 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：
三阴性乳腺癌（TNBC）是最具侵袭性的亚型，具有高转移和死亡率。鉴于缺乏可操作的靶标，如ER和HER2，TNBC仍然是一个未解决的治疗挑战。尽管有高CDK4/6表达水平，由于耐药的出现,在TNBC中抑制CDK4/6的功效受到限制。对CDK4/6抑制的抗性主要由RB1失活介导。由于我们的目标是克服对CDK4/6抑制的抗性，在这项研究中，我们主要使用不表达RB1的细胞系。在筛选CDK4/6抑制后的活化受体酪氨酸激酶（RTKs）后，我们确定了TAM(Tyro3，Axl，和MerTK）RTK是TNBC中至关重要的治疗漏洞。我们证明了用一种新的抑制剂靶向TAM受体，西拉巴替尼,TNBC对CDK4/6抑制剂显著敏感。在延长HER2抑制剂治疗后，HER2+乳腺癌抑制HER2表达，生理转化为TNBC样细胞。我们进一步表明，联合治疗对耐药HER2+乳腺癌也非常有效。在定量蛋白质组学和RNA-seq数据分析之后，我们将研究扩展到了TNBC的免疫分型。鉴于TAM受体在促进免疫抑制肿瘤微环境（TME）形成中的作用，我们进一步证明,CDK4/6抑制剂abemaciclib和sitravatinib的组合改变了TNBC的免疫格局,有利于免疫检查点阻断.总的来说,我们的研究提供了针对TNBC和潜在耐药HER2+乳腺癌的新型高效联合疗法,可迅速转移到临床.
