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
in 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Acrylamides
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Signal Transduction
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Carcinoma, Non-Small-Cell Lung
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Drug Resistance, Neoplasm
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Proto-Oncogene Proteins c-pim-1
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Epithelial-Mesenchymal Transition
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ErbB Receptors
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Glycogen Synthase Kinase 3 beta
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Aniline Compounds
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Lung Neoplasms
Language:
En
Journal:
Cell Death Dis
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: