3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
11 05 2023
11 05 2023
Historique:
received:
11
08
2022
accepted:
01
05
2023
medline:
15
5
2023
pubmed:
12
5
2023
entrez:
11
5
2023
Statut:
epublish
Résumé
Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.
Identifiants
pubmed: 37169941
doi: 10.1038/s42003-023-04889-w
pii: 10.1038/s42003-023-04889-w
pmc: PMC10175489
doi:
Substances chimiques
osimertinib
3C06JJ0Z2O
ErbB Receptors
EC 2.7.10.1
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Protein Kinase Inhibitors
0
TOR Serine-Threonine Kinases
EC 2.7.11.1
Phosphatidylinositols
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
509Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169338
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211052
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204302
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224081
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
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