Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance.
Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.



We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Youngtae
Y
Jeong
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Department of Biology, San Francisco State University, San Francisco, California.
Ngoc T
NT
Hoang
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
Alexander
A
Lovejoy
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
Henning
H
Stehr
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
Aaron M
AM
Newman
Stanford Center for Cancer Systems Biology, Stanford University School of Medicine, Stanford, California.|Department of Radiology, Stanford University School of Medicine, Stanford, California.
Andrew J
AJ
Gentles
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
William
W
Kong
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Department of Biological Sciences, San Jose State University, San Jose, California.
Diana
D
Truong
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
Shanique
S
Martin
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Aadel
A
Chaudhuri
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
Diane
D
Heiser
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
Li
L
Zhou
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Carmen
C
Say
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Justin N
JN
Carter
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Susan M
SM
Hiniker
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.|Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Billy W
BW
Loo
Department of Pathology, Stanford University School of Medicine, Stanford, California.
Robert B
RB
West
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Department of Biochemistry, Stanford University School of Medicine, Stanford, California.|Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California.
Philip
P
Beachy
Division of Oncology, Department of Medicine, Stanford University, Stanford, California.
Ash A
AA
Alizadeh
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California. diehn@stanford.edu.|Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
Maximilian
M
Diehn
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D009361:Neoplasm Invasiveness; D011836:Radiation Tolerance; D013234:Stem Cells / Q000166:cytology / Q000473:pathology; D014132:Trachea / Q000166:cytology / Q000473:pathology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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