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3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Authors
 Ismail M Meraz  ;  Mourad Majidi  ;  Bingliang Fang  ;  Feng Meng  ;  Lihui Gao  ;  RuPing Shao  ;  Renduo Song  ;  Feng Li  ;  Yonathan Lissanu  ;  Huiqin Chen  ;  Min Jin Ha  ;  Qi Wang  ;  Jing Wang  ;  Elizabeth Shpall  ;  Sung Yun Jung  ;  Franziska Haderk  ;  Philippe Gui  ;  Jonathan Wesley Riess  ;  Victor Olivas  ;  Trever G Bivona  ;  Jack A Roth 
Citation
 COMMUNICATIONS BIOLOGY, Vol.6(1) : 509, 2023-05 
Journal Title
COMMUNICATIONS BIOLOGY
Issue Date
2023-05
MeSH
Animals ; Drug Resistance, Neoplasm / genetics ; ErbB Receptors / genetics ; Humans ; Lung Neoplasms* / drug therapy ; Lung Neoplasms* / genetics ; Lung Neoplasms* / pathology ; Mice ; Mutation ; Phosphatidylinositol 3-Kinases ; Phosphatidylinositols ; Protein Kinase Inhibitors / pharmacology ; Protein Kinase Inhibitors / therapeutic use ; Proto-Oncogene Proteins c-akt / genetics ; TOR Serine-Threonine Kinases / genetics
Abstract
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.
Files in This Item:
T202305630.pdf Download
DOI
10.1038/s42003-023-04889-w
Appears in Collections:
4. Graduate School of Public Health (보건대학원) > Graduate School of Public Health (보건대학원) > 1. Journal Papers
Yonsei Authors
Ha, Min Jin(하민진)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/196498
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