3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib.
Ismail M MerazMourad MajidiBingliang FangFeng MengLihui GaoRuPing ShaoRenduo SongFeng LiYonathan LissanuHuiqin ChenMin Jin HaQi WangJing WangElizabeth ShpallSung Yun JungFranziska HaderkPhilippe GuiJonathan Wesley RiessVictor OlivasTrever G BivonaJack A RothPublished in: Communications biology (2023)
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.
Keyphrases
- small cell lung cancer
- epidermal growth factor receptor
- advanced non small cell lung cancer
- tyrosine kinase
- brain metastases
- crispr cas
- multiple sclerosis
- cell death
- gene expression
- transcription factor
- cell cycle arrest
- cell proliferation
- genome wide
- poor prognosis
- induced apoptosis
- oxidative stress
- type diabetes
- climate change
- long non coding rna
- copy number
- dna methylation
- metabolic syndrome
- smoking cessation