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

• Published in: Communications biology 2023-05, Vol.6 (1), p.509-17, Article 509
• Main Authors: Meraz, Ismail M., Majidi, Mourad, Fang, Bingliang, Meng, Feng, Gao, Lihui, Shao, RuPing, Song, Renduo, Li, Feng, Lissanu, Yonathan, Chen, Huiqin, Ha, Min Jin, Wang, Qi, Wang, Jing, Shpall, Elizabeth, Jung, Sung Yun, Haderk, Franziska, Gui, Philippe, Riess, Jonathan Wesley, Olivas, Victor, Bivona, Trever G., Roth, Jack A.
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/106; 13/109; 13/31; 13/51; 14; 59/5; 631/67/1059/2326; 631/67/1612/1350; 64/60; 82; 82/29; 82/58; 96/95; AKT protein; Animals; Biology; Biomedical and Life Sciences; Cell culture; Cell cycle; Cloning; CRISPR; Drug resistance; Drug Resistance, Neoplasm - genetics; Epidermal growth factor receptors; ErbB Receptors - genetics; G1 phase; Humans; Life Sciences; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mutation; Non-small cell lung carcinoma; Nuclear transport; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - genetics; Small cell lung carcinoma; TOR protein; TOR Serine-Threonine Kinases - genetics; Tumors; Xenografts; Yes-associated protein
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-023-04889-w

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. Acquired resistance to osimertinib is driven by PDK1 in preclinical models of non-small cell lung cancer and reveals PDK1 as a potential target for restoring osimertinib sensitivity.