A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia
Issued Date
2022-01-01
Resource Type
ISSN
03906078
eISSN
15928721
Scopus ID
2-s2.0-85099116418
Pubmed ID
33375770
Journal Title
Haematologica
Volume
107
Issue
1
Start Page
77
End Page
85
Rights Holder(s)
SCOPUS
Bibliographic Citation
Haematologica Vol.107 No.1 (2022) , 77-85
Suggested Citation
Damnernsawad A. A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia. Haematologica Vol.107 No.1 (2022) , 77-85. 85. doi:10.3324/haematol.2020.257964 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/86780
Title
A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia
Author(s)
Author's Affiliation
Other Contributor(s)
Abstract
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.