Cancer stem cells (CSCs) are subpopulations of cancer cells within the tumor bulk that have emerged as an attractive therapeutic target for cancer therapy. Accumulating evidence has shown the critical involvement of protein kinase signaling pathways in driving tumor development, cancer relapse, metastasis, and therapeutic resistance. Given that protein kinases are druggable targets for cancer therapy, tremendous efforts are being made to target CSCs with kinase inhibitors. In this review, we summarize the current knowledge and overview of the roles of protein kinases in various signaling pathways in CSC regulation and drug resistance. Furthermore, we provide an update on the preclinical and clinical studies for the use of kinase inhibitors alone or in combination with current therapies for effective cancer therapy. Despite great premises for the use of kinase inhibitors against CSCs, further investigations are needed to evaluate their efficiencies without any adverse effects on normal stem cells.

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