Abstract 1034: Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance

Abstract

Abstract Although lung squamous cell carcinomas (LSCC) comprise a large fraction of non-small cell lung cancers (NSCLCs), their pathogenesis and cell of origin remain incompletely understood and biomarkers that predict therapeutic responses are lacking. Here we describe novel, clinically relevant murine LSCC models driven by inactivation of Trp53 with or without Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal both in vitro and in in vivo, suggesting that Trp53 or Keap1 mutations lead to expansion of mutant stem cell clones. Deletion of Trp53 with or without Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs. However, deletion of Trp53 with or without Keap1 in type II pneumocytes (ATIIs) or bronchioalveolar stem cells (BASCs) produced tumors with the features of adenocarcinoma, indicating that ABSCs represent the likely cell of origin for LSCC in this model. Deletion of Keap1 promoted tumor growth, metastasis and resistance to oxidative stress. N-acetylcysteine (NAC) treatment enhanced tumorsphere formation and metastasis in Keap1WT LSCCs, but not in Keap1-/- LSCCs, suggesting that NRF2-ROS pathway activation is the main mediator of Keap1 loss. Finally, Keap1 deletion induced radioresistance in vitro and in vivo in both LSCCs and lung adenocarcinomas (LUADs). Congruous with these findings, KEAP1/NRF2 mutation status strongly predicted risk of local recurrence in NSCLC patients treated with RT and these mutations could be non-invasively identified in circulating tumor DNA. These data suggest that Trp53 and Keap1 mutations in ABSCs play important roles in LSCC initiation and progression and identify KEAP1/NRF2 mutations as predictive biomarkers that could be used for personalization of therapeutic strategies for NSCLCs, and likely other cancers in which they are recurrently mutated. Citation Format: Youngtae Jeong, Ngoc Hoang, Henning Stehr, Alexander Lovejoy, Andrew Gentles, Aadel Chaudhuri, Billy Loo, Ash Alizadeh, Maximilian Diehn. Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiation resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1034. doi:10.1158/1538-7445.AM2017-1034