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PIM1 kinase promotes EMT-associated osimertinib resistance via regulating GSK3β signaling pathway in EGFR-mutant non-small cell lung cancer.
- Source :
-
Cell death & disease [Cell Death Dis] 2024 Sep 03; Vol. 15 (9), pp. 644. Date of Electronic Publication: 2024 Sep 03. - Publication Year :
- 2024
-
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 3β (GSK3β) 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 GSK3β 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/GSK3β 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Animals
Mice
Cell Line, Tumor
Mutation genetics
Mice, Nude
Snail Family Transcription Factors metabolism
Snail Family Transcription Factors genetics
Indoles
Pyrimidines
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Carcinoma, Non-Small-Cell Lung metabolism
Acrylamides pharmacology
Acrylamides therapeutic use
Proto-Oncogene Proteins c-pim-1 metabolism
Proto-Oncogene Proteins c-pim-1 genetics
Epithelial-Mesenchymal Transition drug effects
Epithelial-Mesenchymal Transition genetics
Aniline Compounds pharmacology
Aniline Compounds therapeutic use
Glycogen Synthase Kinase 3 beta metabolism
Glycogen Synthase Kinase 3 beta genetics
ErbB Receptors metabolism
ErbB Receptors genetics
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Lung Neoplasms pathology
Lung Neoplasms metabolism
Drug Resistance, Neoplasm genetics
Drug Resistance, Neoplasm drug effects
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 15
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 39227379
- Full Text :
- https://doi.org/10.1038/s41419-024-07039-0