PMID- 31548347
OWN - NLM
STAT- MEDLINE
DCOM- 20201001
LR  - 20210514
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 26
IP  - 1
DP  - 2020 Jan 1
TI  - Role of KEAP1/NFE2L2 Mutations in the Chemotherapeutic Response of Patients with 
      Non-Small Cell Lung Cancer.
PG  - 274-281
LID - 10.1158/1078-0432.CCR-19-1237 [doi]
AB  - PURPOSE: Activation of NFE2L2 has been linked to chemoresistance in cell line 
      models. Recently, somatic mutations that activate NFE2L2, including mutations in 
      NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in 
      patients with non-small cell lung cancer (NSCLC). However, the impact of these 
      mutations on chemoresistance remains incompletely explored. EXPERIMENTAL DESIGN: 
      We investigated the effect of Keap1 deletion on chemoresistance in cell lines 
      from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung 
      adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC 
      with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type 
      patients. Time to treatment failure after first-line platinum doublet 
      chemotherapy and overall survival was compared between the two groups. RESULTS: 
      Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased 
      clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In 
      patients with NSCLC, median time to treatment failure (TTF) after first-line 
      chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 
      8.3 months in the control group (P < 0.0001). Median overall survival (OS) was 
      11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control 
      group (P = 0.006). CONCLUSIONS: Keap1 deletion confers chemoresistance in murine 
      lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, 
      NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet 
      chemotherapy compared with matched controls. Novel approaches for improving 
      outcomes in this subset of patients with NSCLC are therefore needed.
CI  - (c)2019 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.
AD  - Department of New Biology, DGIST, Daegu, Republic of Korea.
FAU - Hellyer, Jessica A
AU  - Hellyer JA
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
FAU - Stehr, Henning
AU  - Stehr H
AD  - Department of Pathology, 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 - Niu, Xiaomin
AU  - Niu X
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
AD  - Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao 
      Tong University, Shanghai, China.
FAU - Das, Millie
AU  - Das M
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
AD  - Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California.
FAU - Padda, Sukhmani K
AU  - Padda SK
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
FAU - Ramchandran, Kavitha
AU  - Ramchandran K
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
FAU - Neal, Joel W
AU  - Neal JW
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California.
FAU - Wakelee, Heather
AU  - Wakelee H
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California. diehn@stanford.edu hwakelee@stanford.edu.
FAU - Diehn, Maximilian
AU  - Diehn M
AD  - Stanford Cancer Institute, Stanford University School of Medicine, Stanford, 
      California. diehn@stanford.edu hwakelee@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  - P01 CA139490/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 - 20190923
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
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  - 6PLQ3CP4P3 (Etoposide)
RN  - BG3F62OND5 (Carboplatin)
RN  - P88XT4IS4D (Paclitaxel)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Aged
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Carboplatin/administration & dosage
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/*pathology
MH  - Cisplatin/administration & dosage
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Etoposide/administration & dosage
MH  - Female
MH  - Humans
MH  - Kelch-Like ECH-Associated Protein 1/*genetics/metabolism
MH  - Lung Neoplasms/drug therapy/genetics/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - *Mutation
MH  - NF-E2-Related Factor 2/*genetics/metabolism
MH  - Neoplasm Staging
MH  - Paclitaxel/administration & dosage
MH  - Prognosis
MH  - Spheroids, Cellular
MH  - Survival Rate
PMC - PMC6942632
MID - NIHMS1540518
EDAT- 2019/09/25 06:00
MHDA- 2020/10/02 06:00
PMCR- 2020/07/01
CRDT- 2019/09/25 06:00
PHST- 2019/04/16 00:00 [received]
PHST- 2019/07/12 00:00 [revised]
PHST- 2019/09/16 00:00 [accepted]
PHST- 2019/09/25 06:00 [pubmed]
PHST- 2020/10/02 06:00 [medline]
PHST- 2019/09/25 06:00 [entrez]
PHST- 2020/07/01 00:00 [pmc-release]
AID - 1078-0432.CCR-19-1237 [pii]
AID - 10.1158/1078-0432.CCR-19-1237 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2020 Jan 1;26(1):274-281. doi: 10.1158/1078-0432.CCR-19-1237. 
      Epub 2019 Sep 23.