A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia
Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sora...
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th-mahidol.867802023-06-19T01:09:10Z A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia Damnernsawad A. Mahidol University Medicine Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 and TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of resistance to sorafenib. Analyses of ex vivo drug sensitivity assays in samples from patients with FLT3-ITD AML revealed that lower expression of LZTR1, NF1, and TSC2 correlated with sensitivity to sorafenib. Importantly, MAPK and/or MTOR complex 1 (MTORC1) activity was upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, and sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting the effectiveness of such treatment in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors. 2023-06-18T18:09:10Z 2023-06-18T18:09:10Z 2022-01-01 Article Haematologica Vol.107 No.1 (2022) , 77-85 10.3324/haematol.2020.257964 15928721 03906078 33375770 2-s2.0-85099116418 https://repository.li.mahidol.ac.th/handle/123456789/86780 SCOPUS |
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Medicine Damnernsawad A. A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia |
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Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 and TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of resistance to sorafenib. Analyses of ex vivo drug sensitivity assays in samples from patients with FLT3-ITD AML revealed that lower expression of LZTR1, NF1, and TSC2 correlated with sensitivity to sorafenib. Importantly, MAPK and/or MTOR complex 1 (MTORC1) activity was upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, and sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting the effectiveness of such treatment in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors. |
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Mahidol University |
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Mahidol University Damnernsawad A. |
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Damnernsawad A. |
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Damnernsawad A. |
title |
A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia |
title_short |
A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia |
title_full |
A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia |
title_fullStr |
A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia |
title_full_unstemmed |
A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia |
title_sort |
genome-wide crispr screen identifies regulators of mapk and mtor pathways that mediate resistance to sorafenib in acute myeloid leukemia |
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2023 |
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https://repository.li.mahidol.ac.th/handle/123456789/86780 |
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1781415023371878400 |