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

对抗癌药物的抗性通过引起疾病复发和转移而限制癌症治疗的有效性。虽然化疗耐药性可以由基因突变引起，但治疗诱导的癌细胞适应性反应显著有助于增强药物耐受性。蛋白激酶DYRK1B是细胞增殖的负调节剂，并且已知促进对细胞生长抑制药物和放射疗法的抗性。由于DYRK1B在癌症中的重要作用的证据越来越多，对其细胞功能的了解不足，临床激酶指数将DYRK1B列为未充分研究的“暗激酶”中的优先临床相关激酶。 我们最近的工作确定DYRK1B作为p53的靶基因，其在用DNA损伤诱导抗癌药物治疗后转录上调。此外，我们发现增加DYRK1B水平诱导上皮肿瘤细胞的间充质性状，这是一个与去分化、转移和化疗耐药性相关的过程。该项目旨在阐明DYRK1B作为适应性变化调节剂的作用，癌细胞通过这种适应性变化在细胞应激中生存并抵抗化疗。为此，将对细胞模型进行基因工程改造，用于活细胞成像实验和癌细胞中DYRK1B依赖性效应的转录组学分析。具体而言，我们的目标是阐明DYRK1B的作用的框架内的p53对DNA损伤修复，基因表达和细胞命运的结果的变化的影响。我们将进一步探讨DYRK1B作为癌细胞可塑性调节剂的作用，特别是关注与上皮间质转化相关的表型效应和基因表达变化。为了研究DYRK1B在获得性耐药中的作用，我们将探索通过药理学抑制DYRK1B来使癌细胞对抗癌药物敏感的可能性。通过研究DYRK1B作为p53下游介体的作用，并表征其作为癌细胞可塑性调节剂的功能，我们期望阐明DYRK1B作为暗激酶组的成员，并增强对癌细胞适应性化疗耐药性的机制和功能的理解。

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.