TY - JOUR
T1 - TIE2–FGFR1 interaction induces adaptive PI3K inhibitor resistance by upregulating Aurora A/PlK1/CDK1 signaling in glioblastoma
AU - Li, Xiaolong
AU - Martinez-Ledesma, Emmanuel
AU - Zhang, Chen
AU - Gao, Feng
AU - Zheng, Siyuan
AU - Ding, Jie
AU - Wu, Shaofang
AU - Nguyen, Nghi
AU - Clifford, Stephan C.
AU - Wen, Patrick Y.
AU - Ligon, Keith L.
AU - Alfred Yung, W. K.
AU - Koul, Dimpy
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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 PI3Kspecific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclindependent 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.
AB - 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 PI3Kspecific inhibitor BKM-120. Integrated RNA sequencing and high-throughput drug screening revealed that the Aurora A kinase (Aurora A)/Polo-like kinase 1 (PLK1)/cyclindependent 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.
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U2 - 10.1158/0008-5472.CAN-19-0325
DO - 10.1158/0008-5472.CAN-19-0325
M3 - Article
C2 - 31416846
AN - SCOPUS:85072769202
SN - 0008-5472
VL - 79
SP - 5088
EP - 5101
JO - Cancer Research
JF - Cancer Research
IS - 19
ER -