ES11.01 Lung Adenocarcinoma to Squamous Cell Carcinoma Transdifferentiation and Drug Resistance

Abstract

Lung cancer is notorious for high heterogeneity and strong plasticity, which might contribute to the development of drug resistance. Lineage transition from lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC), as implicated by clinical observation of mixed ADC and SCC pathologies in adenosquamous cell carcinoma (Ad-SCC), reflects strong cancer plasticity and potentially links to drug resistance. Using Genetically Engineered Murine Model (GEMM), we have provided in vivo evidence in supporting the ADC to SCC transdifferentiation (AST): Lkb1-deficient mouse lung ADC transdifferentiates into SCC progressively via pathologically mixed Ad-SCC. Mechanistically, we find that down-regulation of reactive oxygen species (ROS) level through N-acetyl cysteine (NAC) treatment or NRF2 expression inhibits this transition, highlighting the functional importance of ROS in regulating cancer plasticity. Pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect the AST process. Importantly, similar tumor and redox heterogeneity are also found in human LKB1-inactivated lung cancer. In preclinical trials toward metabolic stress, Lkb1-inactivated ADC can develop drug resistance through squamous transdifferentiation. Recent observations in clinic further suggest that such pathological transition might be responsible for resistance to tyrosine kinase inhibitor (TKI) therapy and chemotherapy in relapsed EGFR-mutant lung ADC patients. These findings demonstrate that lung cancer plasticity potentially affects therapeutic response and precision medicine through histological transition.