Epidermal growth factor receptor regulates lineage plasticity driving transformation to small cell lung cancer.
Biochem Biophys Res Commun
; 681: 218-224, 2023 11 12.
Article
em En
| MEDLINE
| ID: mdl-37783120
ABSTRACT
Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) is clinically and genetically heterogeneous, with concurrent RB1/TP53 mutations, indicating an increased risk of transformation into small cell lung cancer (SCLC). When tumor cells convert into a different histological subtype, they lose their dependence on the original oncogenic driver, resulting in therapeutic resistance. However, the molecular details associated with this transformation remain unclear. It has been difficult to define molecular mechanisms of neuroendocrine (NE) transformation in lung cancer due to a lack of pre- and post-transformation clinical samples. In this study, we established a NSCLC cell line with concurrent RB1/TP53 mutations and built corresponding patient-derived xenograft (PDX) models to investigate the mechanisms underlying transformation to SCLC. Studying these PDX models, we demonstrate that EGFR loss facilitates lineage plasticity of lung adenocarcinoma initiated by biallelic mutations of TP53 and RB1. Gene expression analysis of these EGFR knockout tumors revealed altered expression of neuroendocrine synapse-associated lineage genes. There is an increased expression of epigenetic reprogramming factors like Sox2 and gene associated with neural development like NTRK in these EGFR knockout tumors. These findings uncovered the role of EGFR in the acquisition of plasticity, which is the ability of a cell to substantially modify its identity and take on a new phenotype, and defined a novel landscape of potential drivers of NE transformation in lung cancer.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Pulmonar de Células não Pequenas
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Carcinoma de Pequenas Células do Pulmão
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Receptores ErbB
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Adenocarcinoma de Pulmão
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China