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The mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma

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Abstract

Glioblastoma (GBM) is one of the most lethal malignancies in humans, and novel therapeutic strategies are urgently required for its treatment. Tyrosine kinases (TKs) play a pivotal role in intercellular signal transduction and regulate crucial processes of tumor cell biological activities in GBM. This information provides the basis for the molecular target therapies for GBMs. TK inhibitors (TKIs) are expected to be effective therapeutic strategies. However, one important limitation is that GBMs exhibit marked resistance to the TKIs currently available, yet the mechanisms underlying TKI resistance have not been fully characterized. In the current review, we will address the varieties of chemoresistance mechanisms against TKIs in GBM. The mechanisms responsible for TKI refractoriness in GBMs are divided into 2 aspects. The first includes tumor-related concerns, such as a lack of target expression, the multiplicity of targets, redundancy, the appearance of resistant cells, and tumor changes in characteristics. The second includes drug-related concerns, such as inefficient drug effects, delivery, pharmacokinetics, and intolerable side effects. A better understanding of these mechanisms is needed to develop accurate tests to predict the lack of response to TKIs and for developing novel approaches aimed at overcoming the resistance to TKIs.

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Acknowledgments

This work was supported by Grant-in-Aid for Scientific Research (C-23592117) from the Japan Society for the Promotion of Science (M. Nakada) and Takeda Science Foundation (M. Nakada).

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The author has no conflict of interest to declare.

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Authors and Affiliations

  1. Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan

    Mitsutoshi Nakada, Daisuke Kita, Takuya Watanabe, Yutaka Hayashi & Jun-ichiro Hamada

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  1. Mitsutoshi Nakada
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  2. Daisuke Kita
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  3. Takuya Watanabe
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  4. Yutaka Hayashi
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  5. Jun-ichiro Hamada
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Correspondence to Mitsutoshi Nakada.

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Nakada, M., Kita, D., Watanabe, T. et al. The mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma. Brain Tumor Pathol 31, 198–207 (2014). https://doi.org/10.1007/s10014-013-0174-9

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  • DOI: https://doi.org/10.1007/s10014-013-0174-9

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