ROS-regulated phosphorylation of ITPKB by CAMK2G drives cisplatin resistance in ovarian cancer.

Abstract

Platinum resistance accounts for much of the high mortality and morbidity associated with ovarian cancer. Identification of targets with significant clinical translational potential remains an unmet challenge. Through a high-throughput synthetical lethal screening for clinically relevant targets using 290 kinase inhibitors, we identify calcium/calmodulin-dependent protein kinase II gamma (CAMK2G) as a critical vulnerability in cisplatin-resistant ovarian cancer cells. Pharmacologic inhibition of CAMK2G significantly sensitizes ovarian cancer cells to cisplatin treatment in vitro and in vivo. Mechanistically, CAMK2G directly senses ROS, both basal and cisplatin-induced, to control the phosphorylation of ITPKB at serine 174, which directly regulates ITPKB activity to modulate cisplatin-induced ROS stress. Thereby, CAMK2G facilitates the adaptive redox homeostasis upon cisplatin treatment and drives cisplatin resistance. Clinically, upregulation of CAMK2G activity and ITPKB pS174 correlates with cisplatin resistance in human ovarian cancers. This study reveals a key kinase network consisting of CAMK2G and ITPKB for ROS sense and scavenging in ovarian cancer cells to maintain redox homeostasis, offering a potential strategy for cisplatin resistance treatment.

• Authors: Jie Li, Cuimiao Zheng, Mingshuo Wang, Anna D Umano, Qingyuan Dai, Chunyu Zhang, Hua Huang, Qing Yang, Xianzhi Yang, Jingyi Lu, Wenfeng Pan, Bo Li, Shuzhong Yao, Chaoyun Pan
• Journal: Oncogene (Oncogene) Vol. 41 Issue 8 Pg. 1114-1128 (02 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35039634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Cisplatin

Topics

• Cisplatin