TY - JOUR
T1 - A genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways that mediate resistance to sorafenib in acute myeloid leukemia
AU - Damnernsawad, Alisa
AU - Bottomly, Daniel
AU - Kurtz, Stephen E.
AU - Eide, Christopher A.
AU - McWeeney, Shannon K.
AU - Tyner, Jeffrey W.
AU - Nechiporuk, Tamilla
N1 - Funding Information:
This study was supported by grants from the National Cancer Institute (1U01CA217862, 1U54CA224019, 3P30CA069533-18S5). JWT received grants from the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, and the National Cancer Institute (1R01CA183947). TN is supported by grant R50 CA251708-01.
Publisher Copyright:
© 2022 Ferrata Storti Foundation
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099116418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099116418&partnerID=8YFLogxK
U2 - 10.3324/haematol.2020.257964
DO - 10.3324/haematol.2020.257964
M3 - Article
C2 - 33375770
AN - SCOPUS:85099116418
SN - 0390-6078
VL - 107
SP - 77
EP - 85
JO - Haematologica
JF - Haematologica
IS - 1
ER -