KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer.

Elife
Authors
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 (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). 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.

Year of Publication
2017
Journal
Elife
Volume
6
Date Published
2017 Feb 01
ISSN
2050-084X
DOI
10.7554/eLife.18970
PubMed ID
28145866
PubMed Central ID
PMC5305212
Links
Grant list
U01 CA199253 / CA / NCI NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
F32 CA189306 / CA / NCI NIH HHS / United States
UL1 TR001102 / TR / NCATS NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States