A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia
Year: 2020
Type: article
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 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly, MAPK and/or MTOR complex1 (MTORC1) activity were upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, or sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.
Source: Haematologica
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,157
Awards: G1040166590, G1086801703, Mechanisms of Drug Resistance in Acute Myeloid Leukemia, Functional Genomic Discovery of Pathway Targeted and Immune Modulatory Therapeutic Combinations in Hematologic Malignancies, Architecture and Trajectory of Acquired Resistance to Therapy in AML, Mechanisms of venetoclax combination activity in acute myeloid leukemia, OHSU Knight Cancer Institute, G937892673
OpenAlex ID: W3116843665