Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

Xinran Li, Victor C. Y. Mak, Yuan Zhou, Chao Wang, Esther S. Y. Wong, Rakesh Sharma, Yiling Lu, Annie N. Y. Cheung, Gordon B. Mills and Lydia W. T. Cheung ()
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Xinran Li: The University of Hong Kong
Victor C. Y. Mak: The University of Hong Kong
Yuan Zhou: The University of Hong Kong
Chao Wang: Obstetrics and Gynecology Hospital, Fudan University
Esther S. Y. Wong: The University of Hong Kong
Rakesh Sharma: The University of Hong Kong
Yiling Lu: University of Texas MD Anderson Cancer Center
Annie N. Y. Cheung: The University of Hong Kong
Gordon B. Mills: Oregon Health & Science University
Lydia W. T. Cheung: The University of Hong Kong

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.

Date: 2019
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DOI: 10.1038/s41467-019-08574-7

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