In:
eLife, eLife Sciences Publications, Ltd, Vol. 6 ( 2017-02-01)
Abstract:
Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs ( 〈 xref ref-type="bibr" rid="bib2" 〉 Balak et al., 2006 〈 /xref 〉 ; 〈 xref ref-type="bibr" rid="bib30" 〉 Kosaka et al., 2006 〈 /xref 〉 ; 〈 xref ref-type="bibr" rid="bib37" 〉 Rudin et al., 2013 〈 /xref 〉 ; 〈 xref ref-type="bibr" rid="bib45" 〉 Wagle et al., 2011 〈 /xref 〉 ). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.18970.001
DOI:
10.7554/eLife.18970.002
DOI:
10.7554/eLife.18970.003
DOI:
10.7554/eLife.18970.004
DOI:
10.7554/eLife.18970.005
DOI:
10.7554/eLife.18970.006
DOI:
10.7554/eLife.18970.007
DOI:
10.7554/eLife.18970.008
DOI:
10.7554/eLife.18970.009
DOI:
10.7554/eLife.18970.010
DOI:
10.7554/eLife.18970.011
DOI:
10.7554/eLife.18970.012
DOI:
10.7554/eLife.18970.013
DOI:
10.7554/eLife.18970.014
DOI:
10.7554/eLife.18970.015
DOI:
10.7554/eLife.18970.016
DOI:
10.7554/eLife.18970.017
DOI:
10.7554/eLife.18970.018
DOI:
10.7554/eLife.18970.019
DOI:
10.7554/eLife.18970.020
DOI:
10.7554/eLife.18970.021
DOI:
10.7554/eLife.18970.022
DOI:
10.7554/eLife.18970.023
DOI:
10.7554/eLife.18970.024
DOI:
10.7554/eLife.18970.025
DOI:
10.7554/eLife.18970.026
DOI:
10.7554/eLife.18970.027
DOI:
10.7554/eLife.18970.028
DOI:
10.7554/eLife.18970.029
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2017
detail.hit.zdb_id:
2687154-3
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