Comprehensive multi-omics analysis revealed WEE1 as a synergistic lethal target with hyperthermia through CDK super-activation

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in epithelial ovarian cancer (EOC) is still controversial partly because of the poorly understood mechanism of action. Further an understanding of the underlying mechanisms could identify potential combination therapies. Here, we conduct a comprehensive multi-omics study (transcriptiome, proteome, and phosphoproteome) upon hyperthermia (HT) in ovarian cancer cells. Unbiased trans-omics approach deciphered a unique hyperthermia- induced molecular panorama and demonstrated rapid alterations in protein phosphorylation as the primary cell response upon HT. Based on the phospho-signature, we identified CDK kinases to be hyperactivated and responsible for the global signaling landscape upon HT. Molecular and functional experiments demonstrated the dynamic and reversible CDK activity, subsequent replication arrest, and early mitotic entry after HT. A follow-up drug screen identified WEE1 inhibition to synergistically kills cancer cells with HT. An in-house developed miniaturized devise delivered proof-of-concept that the combination of hyperthermia with WEE1i leads to dramatic anti-tumor responses in vivo. These findings provide new insights into how to improve the effectiveness of HIPEC in EOC.