Tie2-FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma.

Abstract

PI3K-targeting therapy represents one of the most sought-after therapies for glioblastoma (GBM). Several small-molecule inhibitors have been evaluated in clinical trials, however, the emergence of resistance limits treatment potential. Here, we generated a patient-derived glioma sphere-forming cell (GSC) xenograft model resistant to the PI3K-specific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclin-dependent kinase 1 (CDK1) signaling pathway was the main driver of PI3K inhibitor resistance in the resistant xenografts. Aurora kinase was upregulated and pCDK1 was downregulated in resistant tumors from both xenografts and tumor tissues from patients treated with the PI3K inhibitor. Mechanistically, the tyrosine kinase receptor Tie2 physically interacted with FGFR1, promoting STAT3 phosphorylation and binding to the AURKA promoter, which increased Aurora A expression in resistant GSCs. Concurrent inhibition of Aurora A and PI3K signaling overcame PI3K inhibitor-induced resistance. This study offers a proof of concept to target PI3K and the collateral-activated pathway to improve GBM therapy. SIGNIFICANCE: These findings provide novel insights into the mechanisms of PI3K inhibitor resistance in glioblastoma.

• Authors: Xiaolong Li, Emmanuel Martinez-Ledesma, Chen Zhang, Feng Gao, Siyuan Zheng, Jie Ding, Shaofang Wu, Nghi Nguyen, Stephan C Clifford, Patrick Y Wen, Keith L Ligon, W K Alfred Yung, Dimpy Koul
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 19 Pg. 5088-5101 (10 01 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 31416846 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1
• Receptor, TIE-2
• TEK protein, human
• AURKA protein, human
• Aurora Kinase A
• Protein Serine-Threonine Kinases
• CDC2 Protein Kinase
• CDK1 protein, human

Topics

• Animals
• Aurora Kinase A (metabolism)
• CDC2 Protein Kinase (metabolism)
• Cell Cycle Proteins (metabolism)
• Drug Resistance, Neoplasm (physiology)
• Glioblastoma (pathology)
• Heterografts
• Humans
• Male
• Mice
• Mice, Nude
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Receptor, Fibroblast Growth Factor, Type 1 (metabolism)
• Receptor, TIE-2 (metabolism)
• Signal Transduction (physiology)
• Up-Regulation
• Polo-Like Kinase 1