Enhancing chemotherapeutic efficacy in triple-negative breast cancer via DSTYK silence

项目摘要 乳腺癌是女性中最常见的癌症，超过15%的新发癌症是由乳腺癌引起的 癌症病例，约占美国所有癌症相关死亡人数的6.9%。治疗的一个主要原因 乳腺癌的失败是对化疗产生耐药性，特别是对三联化疗 阴性乳腺癌(TNBC)，一种被认为更具侵袭性和 与其他类型的乳腺癌相比，预后更差。因此，如何克服 化疗耐药性是提高TNBC患者预期寿命的主要挑战。 初步数据显示，慢性前列腺癌治疗后存活的TNBC细胞 化疗药物显示一种特殊的蛋白激酶DUAL的表达显著增加 丝氨酸/苏氨酸和酪氨酸蛋白激酶(DSTYK)，比未经处理的亲本细胞。 此外，从体外和体内结果来看，我们发现DSTYK和DSTYK的敲除都 Exosome介导的DSTYK沉默可诱导药物耐药细胞的凋亡 治疗。这一新的发现表明，DSTYK发挥着以前未知的重要作用 在促进化疗耐药性方面的作用。这项提议的目的是阐明新的角色 以及DSTYK调节TNBC细胞化疗耐药的机制。 进一步探讨Exosome介导的DSTYK沉默在TNBC化疗中的可能性 临床前模型。我们假设DSTYK是化疗诱导的新靶点。 TNBC细胞死亡。我们将用三个具体目标来检验我们的假设。在目标1中，我们将调查 DSTYK促进TNBC细胞耐药的机制。在目标2中，我们将 建立DSTYK作为临床TNBC预后的生物标志物。在目标3中，我们将评估 DSTYK-siRNA-exosome在化疗中的疗效。我们设计了外切体 含有针对DSTYK的siRNA，可以特异性地靶向TNBC细胞。我们发现了这些 工程外切体能显著促进肿瘤消退并抑制两者的转移 用药物治疗的细胞和原位模型。圆满完成拟议的研究 将为DSTYK在TNBC细胞化疗耐药中的作用提供基本的见解 将为外切体介导的靶向策略的发展奠定必要的基础 DSTYK能显著改善临床TNBC化疗。

Project Abstract Breast cancer, the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple- negative breast cancer (TNBC), a type of breast cancer considered to be more aggressive and have a poorer prognosis than other types of breast cancer. Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of TNBC patients. Preliminary data demonstrate that TNBC cells surviving from the chronic treatment of chemotherapeutic drugs show significantly higher expression of a special protein kinase, dual serine/threonine and tyrosine protein kinase (DSTYK), than parental cells without treatment. Additionally, from both in vitro and in vivo results, we found that both the knockout of DSTYK and exosome-mediated DSTYK silence can lead to the apoptosis of chemoresistant cells upon drug treatment. This novel finding suggests that DSTYK exerts a previously unknown and important role in promoting chemoresistance. The objective of this proposal is to elucidate the novel role and the underpinning mechanism of DSTYK in regulating chemoresistance in TNBC cells and further explore the potential of exosome-mediated DSTYK silence in TNBC chemotherapy with preclinical models. We hypothesize that DSTYK is a novel target for chemotherapy to induce TNBC cell death. We will test our hypothesis with three specific aims. In Aim 1, we will investigate the mechanism by which DSTYK promotes chemoresistance in TNBC cells. In Aim 2, we will establish DSTYK as a prognostic biomarker in clinical TNBC. In Aim 3, we will evaluate the therapeutic benefit of DSTYK-siRNA-exosomes in chemotherapy. We engineered exosomes containing siRNA against DSTYK that can specifically target TNBC cells. We found these engineered exosomes can significantly promote tumor regression and inhibit metastasis in both cellular and orthotopic models treated with drugs. Successful completion of the proposed studies will provide fundamental insights into the role of DSTYK in chemoresistance in TNBC cells and will lay the essential foundation for the development of an exosome-mediated strategy targeting DSTYK to significantly improve clinical TNBC chemotherapy.