Functional and mechanistic studies on the transition from adenocarcinoma to squamous cell carcinomain lung cancer drug resistance

Abstract

Lung cancer, featured with strong heterogeneity and plasticity, is the most devastating diseaseworldwide. Based on histological classification, lung cancer can be categorized as small cell lung cancer(SCLC) and non-small cell lung cancer (NSCLC), among which the latter could be further classified into lungadenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC). Mixed pathologies ofADC and SCC (Adenosquamous Cell Carcinoma, Ad-SCC) or mixed SCLC with ADC and/or SCC pathology(mixed SCLC) have been consistently observed in clinic. Lung Ad-SCC is about 4%~10% of NSCLC. Recentclinical studies have shown that epidermal growth factor receptor (EGFR) mutant lung ADC could transition to SCC in relapsed patients failed from chemotherapy, targeted therapy or immunotherapy. Studies of liver kinaseB1 (Lkb1)-defi cient mouse model have provided convincing evidence in supporting that lung ADC derived fromclub cells or AT2 cells (Alveolar Epithelial Type 2 Cells) is prone to squamous transition, and the mixed AdSCC is identified as the intermediate stage. Mechanistic studies demonstrate that uncontrolled accumulation ofexcessive oxidative stress resulted from extracellular matrix depletion and metabolic reprogramming somehowtriggers the up-regulation of SCC-lineage specific transcription factor, p63, which eventually promotes thesquamous transition. Such transition confers lung tumors with drug resistance in mouse models. This review willsummarize current research progress of the transition from lung ADC to SCC as well as its correlation with drugresistance acquisition, which hopefully provides novel insights into lung cancer plasticity and drug resistance.

Keywords

• lung cancer plasticity
• lung adc-to-scc transition
• targeted therapy resistance
• animalmodel
• molecular mechanism