Role of DYRK1B in DNA damage repair and chemoresistance in cancer cells

DYRK1B 在癌细胞 DNA 损伤修复和化疗耐药中的作用

• 批准号: 520339551
• 负责人: Professor Dr. Walter Becker
• 金额: --
• 依托单位: Institut für Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/520339551?language=en
• 关键词: Role; DYRK1B; DNA; damage; repair

Resistance to anticancer drugs restricts the effectiveness of cancer treatments by causing disease relapse and metastasis. While chemoresistance can result from genetic mutations, therapy-induced adaptive responses of cancer cells contribute significantly to enhanced drug tolerance. The protein kinase DYRK1B is a negative regulator of cell proliferation and is known to promote resistance to cytostatic drugs and radiotherapy. Owing to the disparity of the increasing evidence for an important role of DYRK1B in cancer and the insufficient understanding of its cellular function, the Clinical Kinase Index ranks DYRK1B as a prioritized clinically relevant kinase among the understudied “dark kinases”. Our recent work identified DYRK1B as a target gene of p53 that is transcriptionally upregulated upon treatment with DNA damage-inducing anticancer drugs. Furthermore, we found that increased DYRK1B levels induced mesenchymal traits in epithelial tumor cells, a process related to dedifferentiation, metastasis and chemoresistance. The proposed project aims to clarify the role of DYRK1B as a regulator of the adaptive changes by which cancer cells survive cellular stresses and resist chemotherapy. To this end, cell models will be genetically engineered for live cell imaging experiments and transcriptomic analyses of DYRK1B-dependend effects in cancer cells. Specifically, we aim to elucidate the role of DYRK1B within the framework of p53 effects on DNA damage repair, changes in gene expression and cell fate outcomes. We will further address the role of DYRK1B as a modulator of cancer cell plasticity, in particular focusing on the phenotypic effects and the changes in gene expression that are associated with epithelial mesenchymal transition. To scrutinize the role of DYRK1B in acquired drug resistance, we will explore the possibility to sensitize cancer cells to anticancer drugs by pharmacological inhibition of DYRK1B. By investigating the role of DYRK1B as a downstream mediator of p53 and characterizing its functions as a regulator of cancer cell plasticity, we expect to illuminate DYRK1B as a member of the dark kinome and to enhance the mechanistic and functional understanding of adaptive chemoresistance in cancer cells.

抗癌药物的耐药性会导致疾病复发和转移，从而限制癌症治疗的有效性。虽然化疗耐药可以由基因突变引起，但治疗诱导的癌细胞适应性反应对提高药物耐受性做出了重大贡献。蛋白激酶DYRK1B是细胞增殖的负性调节因子，已知会增加对细胞抑制药物和放射治疗的耐药性。由于越来越多的证据表明DYRK1B在癌症中起着重要的作用，而且对其细胞功能的了解还不够充分，临床激酶指数将DYRK1B列为研究不足的“暗激酶”中优先考虑的临床相关蛋白。我们最近的工作确定DYRK1B是P53的一个靶基因，在DNA损伤诱导的抗癌药物治疗后，它在转录上上调。此外，我们还发现，DYRK1B水平的增加诱导了上皮性肿瘤细胞的间质特征，这一过程与去分化、转移和化疗耐药有关。这项拟议的项目旨在阐明DYRK1B作为癌细胞在细胞压力下生存和抵抗化疗的适应性变化的调节器所起的作用。为此，将对细胞模型进行基因工程，以进行活细胞成像实验和对癌细胞中DYRK1B依赖的效应进行转录分析。具体地说，我们的目的是在p53对DNA损伤修复、基因表达变化和细胞命运结果的影响的框架内阐明DYRK1B的作用。我们将进一步探讨DYRK1B作为癌细胞可塑性调节剂的作用，特别是与上皮间充质转化相关的表型效应和基因表达的变化。为了研究DYRK1B在获得性耐药中的作用，我们将探索通过对DYRK1B的药理抑制来增强癌细胞对抗癌药物敏感性的可能性。通过研究DYRK1B作为P53下游介体的作用及其作为癌细胞可塑性调节因子的功能，我们期望阐明DYRK1B是暗激动组的一员，并加强对癌细胞适应性化疗耐药的机制和功能的了解。