PMID- 27663899
OWN - NLM
STAT- MEDLINE
DCOM- 20171102
LR  - 20220419
IS  - 2159-8290 (Electronic)
IS  - 2159-8274 (Print)
IS  - 2159-8274 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Jan
TI  - Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development 
      and Radiation Resistance.
PG  - 86-101
LID - 10.1158/2159-8290.CD-16-0127 [doi]
AB  - 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. SIGNIFICANCE: 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. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 
      1.
CI  - (c)2016 American Association for Cancer Research.
FAU - Jeong, Youngtae
AU  - Jeong Y
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, California.
FAU - Hoang, Ngoc T
AU  - Hoang NT
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
AD  - Department of Biology, San Francisco State University, San Francisco, California.
FAU - Lovejoy, Alexander
AU  - Lovejoy A
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
FAU - Stehr, Henning
AU  - Stehr H
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
FAU - Newman, Aaron M
AU  - Newman AM
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
FAU - Gentles, Andrew J
AU  - Gentles AJ
AD  - Stanford Center for Cancer Systems Biology, Stanford University School of 
      Medicine, Stanford, California.
AD  - Department of Radiology, Stanford University School of Medicine, Stanford, 
      California.
FAU - Kong, William
AU  - Kong W
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
FAU - Truong, Diana
AU  - Truong D
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
AD  - Department of Biological Sciences, San Jose State University, San Jose, 
      California.
FAU - Martin, Shanique
AU  - Martin S
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
FAU - Chaudhuri, Aadel
AU  - Chaudhuri A
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, California.
FAU - Heiser, Diane
AU  - Heiser D
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
FAU - Zhou, Li
AU  - Zhou L
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
FAU - Say, Carmen
AU  - Say C
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, California.
FAU - Carter, Justin N
AU  - Carter JN
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, California.
FAU - Hiniker, Susan M
AU  - Hiniker SM
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, California.
FAU - Loo, Billy W Jr
AU  - Loo BW Jr
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, California.
FAU - West, Robert B
AU  - West RB
AD  - Department of Pathology, Stanford University School of Medicine, Stanford, 
      California.
FAU - Beachy, Philip
AU  - Beachy P
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
AD  - Department of Biochemistry, Stanford University School of Medicine, Stanford, 
      California.
AD  - Howard Hughes Medical Institute, Stanford University School of Medicine, 
      Stanford, California.
FAU - Alizadeh, Ash A
AU  - Alizadeh AA
AD  - Division of Oncology, Department of Medicine, Stanford University, Stanford, 
      California.
FAU - Diehn, Maximilian
AU  - Diehn M
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California. diehn@stanford.edu.
AD  - Institute for Stem Cell Biology and Regenerative Medicine, Stanford University 
      School of Medicine, Stanford, California.
AD  - Department of Radiation Oncology, Stanford University School of Medicine, 
      Stanford, California.
LA  - eng
GR  - DP2 CA186569/CA/NCI NIH HHS/United States
GR  - T32 CA009302/CA/NCI NIH HHS/United States
GR  - T32 CA121940/CA/NCI NIH HHS/United States
GR  - U01 CA194389/CA/NCI NIH HHS/United States
GR  - P01 CA139490/CA/NCI NIH HHS/United States
GR  - P30 CA124435/CA/NCI NIH HHS/United States
GR  - P30 CA147933/CA/NCI NIH HHS/United States
GR  - R01 CA188298/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160923
PL  - United States
TA  - Cancer Discov
JT  - Cancer discovery
JID - 101561693
RN  - 0 (KEAP1 protein, human)
RN  - 0 (Kelch-Like ECH-Associated Protein 1)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Carcinoma, Squamous Cell/*genetics/pathology/radiotherapy
MH  - Cell Line, Tumor
MH  - Cell Self Renewal
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/*genetics
MH  - Lung Neoplasms/*genetics/pathology/radiotherapy
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Mutation
MH  - NF-E2-Related Factor 2/*genetics
MH  - Neoplasm Invasiveness
MH  - *Radiation Tolerance
MH  - Stem Cells/cytology/pathology
MH  - Trachea/cytology/*pathology
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Protein p53/*genetics
PMC - PMC5222718
MID - NIHMS827177
COIS- of potential conflicts of interest - A.M.N., A.A.A., and M.D. are co-inventors on 
      patent applications related to CAPP-Seq. A.L. is currently an employee of Roche. 
      A.M.N., A.A.A., and M.D. are consultants for Roche. Other authors disclose no 
      conflicts of interest.
EDAT- 2016/09/25 06:00
MHDA- 2017/11/03 06:00
PMCR- 2018/01/01
CRDT- 2016/09/25 06:00
PHST- 2016/01/28 00:00 [received]
PHST- 2016/09/20 00:00 [revised]
PHST- 2016/09/22 00:00 [accepted]
PHST- 2016/09/25 06:00 [pubmed]
PHST- 2017/11/03 06:00 [medline]
PHST- 2016/09/25 06:00 [entrez]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 2159-8290.CD-16-0127 [pii]
AID - 10.1158/2159-8290.CD-16-0127 [doi]
PST - ppublish
SO  - Cancer Discov. 2017 Jan;7(1):86-101. doi: 10.1158/2159-8290.CD-16-0127. Epub 2016 
      Sep 23.