KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer.
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 ofKEAP1, 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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Elsa B
EB
Krall
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Belinda
B
Wang
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Diana M
DM
Munoz
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Nina
N
Ilic
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Srivatsan
S
Raghavan
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Matthew J
MJ
Niederst
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Kristine
K
Yu
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
David A
DA
Ruddy
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Andrew J
AJ
Aguirre
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Jong Wook
JW
Kim
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Amanda J
AJ
Redig
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
Justin F
JF
Gainor
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Juliet A
JA
Williams
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.|Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
John M
JM
Asara
Broad Institute of Harvard and MIT, Cambridge, United States.
John G
JG
Doench
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
Pasi A
PA
Janne
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
Alice T
AT
Shaw
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Robert E
RE
McDonald Iii
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Jeffrey A
JA
Engelman
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Frank
F
Stegmeier
Oncology Disease Area, Novartis Institute for Biomedical Research, Cambridge, United States.
Michael R
MR
Schlabach
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.|Broad Institute of Harvard and MIT, Cambridge, United States.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, United States.
William C
0000-0003-2840-9791
WC
Hahn
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D055786:Gene Knockout Techniques; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics*; D008175:Lung Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1
CRISPR-Cas9; cancer biology; drug resistance; human; lung cancer