PIM1 kinase promotes EMT-associated osimertinib resistance via regulating GSK3ß signaling pathway in EGFR-mutant non-small cell lung cancer.
Cell Death Dis
; 15(9): 644, 2024 Sep 03.
Article
em En
| MEDLINE
| ID: mdl-39227379
ABSTRACT
Acquired resistance is inevitable in the treatment of non-small cell lung cancer (NSCLC) with osimertinib, and one of the primary mechanisms responsible for this resistance is the epithelial-mesenchymal transition (EMT). We identify upregulation of the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and functional inactivation of glycogen synthase kinase 3ß (GSK3ß) as drivers of EMT-associated osimertinib resistance. Upregulation of PIM1 promotes the growth, invasion, and resistance of osimertinib-resistant cells and is significantly correlated with EMT molecules expression. Functionally, PIM1 suppresses the ubiquitin-proteasome degradation of snail family transcriptional repressor 1 (SNAIL) and snail family transcriptional repressor 2 (SLUG) by deactivating GSK3ß through phosphorylation. The stability and accumulation of SNAIL and SLUG facilitate EMT and encourage osimertinib resistance. Furthermore, treatment with PIM1 inhibitors prevents EMT progression and re-sensitizes osimertinib-resistant NSCLC cells to osimertinib. PIM1/GSK3ß signaling is activated in clinical samples of osimertinib-resistant NSCLC, and dual epidermal growth factor receptor (EGFR)/PIM1 blockade synergistically reverse osimertinib-resistant NSCLC in vivo. These data identify PIM1 as a driver of EMT-associated osimertinib-resistant NSCLC cells and predict that PIM1 inhibitors and osimertinib combination therapy will provide clinical benefit in patients with EGFR-mutant NSCLC.
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Base de dados:
MEDLINE
Assunto principal:
Acrilamidas
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Transdução de Sinais
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Carcinoma Pulmonar de Células não Pequenas
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Resistencia a Medicamentos Antineoplásicos
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Proteínas Proto-Oncogênicas c-pim-1
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Transição Epitelial-Mesenquimal
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Receptores ErbB
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Glicogênio Sintase Quinase 3 beta
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Compostos de Anilina
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Neoplasias Pulmonares
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China