EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer.
Proc Natl Acad Sci U S A
; 121(23): e2317790121, 2024 Jun 04.
Article
em En
| MEDLINE
| ID: mdl-38814866
ABSTRACT
The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transformação Celular Neoplásica
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Carcinoma Pulmonar de Células não Pequenas
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Cloridrato de Erlotinib
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Neoplasias Pulmonares
Limite:
Animals
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
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Proc. Natl. Acad. Sci. U. S. A
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Proceedings of the national academy of sciences of the United States of America
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China