@article{45a4529f6da9406c873cf02d6899cf5f,
title = "Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer",
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.",
author = "Xinran Li and Mak, {Victor C.Y.} and Yuan Zhou and Chao Wang and Wong, {Esther S.Y.} and Rakesh Sharma and Yiling Lu and Cheung, {Annie N.Y.} and Mills, {Gordon B.} and Cheung, {Lydia W.T.}",
note = "Funding Information: This study was supported by Hong Kong Research Grants Council (#27103616) and National Natural Science Foundation of China (#81703066) to L.W.C.; NCI (1P50 CA217685-01, 1U01 CA217842-01), Ovarian Cancer Research Foundation, a kind gift from the Adelson Medical Research Foundation to G.B.M.; Health and Medical Research Fund, Hong Kong Special Administrative Region (#03143006) to A.N.C.; National Natural Science Foundation of China (#81772777) and Shanghai Pujiang Program (17PJ1401400) to C.W. The authors would like to thank the RPPA Core Facility and the Characterized Cell Line Core Facility (funded by NCI #CA016672) of the MD Anderson Cancer Center (Houston, TX) and Dr. Takashi Saito (RIKEN Center for Integrative Medical Science, Japan), Dr. Gen-sheng Feng (University of California San Diego, USA), Dr. Susan Meakin (University of Western Ontario, Canada) for generously providing the wild-type GAB2 plasmids. We also thank the Faculty Core Facility of the LKS Faculty of Medicine HKU for the help with flow cytometry and confocal microscopy. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-08574-7",
language = "English (US)",
volume = "10",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}