A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia
Alisa Damnernsawad,
Daniel Bottomly,
Stephen E. Kurtz,
Christopher A. Eide,
Shannon K. McWeeney,
Jeffrey W. Tyner,
Tamilla Nechiporuk
Affiliations
Alisa Damnernsawad
Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Department of Biology, Faculty of Science, Mahidol University, Bangkok
Daniel Bottomly
Division of Bioinformatics and Computational Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
Stephen E. Kurtz
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
Christopher A. Eide
Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
Shannon K. McWeeney
Division of Bioinformatics and Computational Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
Jeffrey W. Tyner
Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
Tamilla Nechiporuk
Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR
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 genomewide 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.
