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.
Article and author information
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.
Reviewing Editor
- Martin McMahon, University of Utah Medical Schoo, United States
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.
Version history
- Received: June 21, 2016
- Accepted: January 31, 2017
- Accepted Manuscript published: February 1, 2017 (version 1)
- Version of Record published: February 13, 2017 (version 2)
- Version of Record updated: October 31, 2017 (version 3)
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.
Metrics
-
- 7,629
- views
-
- 1,641
- downloads
-
- 114
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
eLife 6:e18970.
https://doi.org/10.7554/eLife.18970
Further reading
-
- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
