KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
- KSQ Therapeutics, United States
- Dana-Farber Cancer Institute, United States
- Novartis Institute for Biomedical Research, United States
- Massachusetts General Hospital, United States
- Beth Israel Deaconess Medical Center, United States
- Broad Institute of Harvard and MIT, 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 occurs1-4. 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.
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Author details
Funding
National Cancer Institute (R01 CA130998)
- William C Hahn
Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer
- Andrew J Aguirre
Perry S. Levy Endowed Fellowship
- Andrew J Aguirre
Harvard Catalyst and Harvard Clinical and Translational Science Center (UL1 TR001102)
- Andrew J Aguirre
National Cancer Institute (U01 CA176058)
- William C Hahn
National Cancer Institute (U01 CA199253)
- William C Hahn
Hope Funds for Cancer Research (Postdoctoral Fellowship HFCR-11-03-03)
- Elsa Beyer Krall
National Institutes of Health (Postdoctoral Fellowship F32 CA189306)
- Elsa Beyer Krall
Susan G. Komen Foundation (Postdoctoral Fellowship PDF12230602)
- Nina Ilic
Terri Brodeur Breast Cancer Foundation (Postdoctoral Fellowship)
- Nina Ilic
Pancreatic Cancer Action Network (Samuel Stroum Fellowship)
- Andrew J Aguirre
American Society of Clinical Oncology (Young Investigator Award)
- Andrew J Aguirre
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were maintained and handled in accordance with the Novartis Institutes for Biomedical Research (NIBR) Animal Care and Use Committee protocols and regulations.
Copyright
© 2017, Krall et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
eLife 6:e18970.
https://doi.org/10.7554/eLife.18970
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