Publication Date
5-11-2023
Journal
Communications Biology
DOI
10.1038/s42003-023-04889-w
PMID
37169941
PMCID
PMC10175489
PubMedCentral® Posted Date
5-11-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Mice, Animals, Humans, Lung Neoplasms, ErbB Receptors, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Protein Kinase Inhibitors, Drug Resistance, Neoplasm, Mutation, TOR Serine-Threonine Kinases, Phosphatidylinositols
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.
Included in
Biomedical Informatics Commons, Diseases Commons, Medical Sciences Commons, Oncology Commons
Comments
This article has been corrected. See Commun Biol. 2023 Jun 6;6:608.
Associated Data