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

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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.