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Elife. 2017 Feb 1;6. pii: e18970. doi: 10.7554/eLife.18970.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
2
Broad Institute of Harvard and MIT, Cambridge, United States.
3
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
4
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
5
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
6
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
7
Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.

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.

KEYWORDS:

CRISPR-Cas9; cancer biology; drug resistance; human; lung cancer

PMID:
28145866
PMCID:
PMC5305212
DOI:
10.7554/eLife.18970
[Indexed for MEDLINE]
Free PMC Article

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