Format

Send to

Choose Destination
Cancer Discov. 2017 Jan;7(1):86-101. doi: 10.1158/2159-8290.CD-16-0127. Epub 2016 Sep 23.

Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance.

Author information

1
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
3
Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California.
4
Department of Biology, San Francisco State University, San Francisco, California.
5
Stanford Center for Cancer Systems Biology, Stanford University School of Medicine, Stanford, California.
6
Department of Radiology, Stanford University School of Medicine, Stanford, California.
7
Department of Biological Sciences, San Jose State University, San Jose, California.
8
Department of Pathology, Stanford University School of Medicine, Stanford, California.
9
Department of Biochemistry, Stanford University School of Medicine, Stanford, California.
10
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California.
11
Division of Oncology, Department of Medicine, Stanford University, Stanford, California.
12
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California. diehn@stanford.edu.

Abstract

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. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

PMID:
27663899
PMCID:
PMC5222718
DOI:
10.1158/2159-8290.CD-16-0127
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

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.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center