Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance

Youngtae Jeong, Ngoc T. Hoang, Alexander Lovejoy, Henning Stehr, Aaron M. Newman, Andrew J. Gentles, William Kong, Diana Truong, Shanique Martin, Aadel Chaudhuri, Diane Heiser, Li Zhou, Carmen Say, Justin N. Carter, Susan M. Hiniker, Billy W. Loo, Robert B. West, Philip Beachy, Ash A. Alizadeh, Maximilian Diehn

Research output: Contribution to journalArticlepeer-review

249 Scopus citations

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.

Original languageEnglish
Pages (from-to)86-101
Number of pages16
JournalCancer Discovery
Volume7
Issue number1
DOIs
StatePublished - Jan 2017

Bibliographical note

Publisher Copyright:
© 2017 American Association for Cancer Research.

Fingerprint

Dive into the research topics of 'Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance'. Together they form a unique fingerprint.

Cite this