Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC.

Platinum-Resistant Ovarian Cancer Is Vulnerable to the cJUN-XRCC4 Pathway Inhibition.

DNA double-strand breaks (DSBs) caused by platinum drugs are dangerous lesions that kill cancer cells in chemotherapy. Repair of DSB by homologous recombination (HR) and nonhomologous end joining (NHEJ) is frequently associated with platinum resistance in ovarian cancer. While the role of the HR pathway and HR-targeting strategy in platinum resistance is well studied, dissecting and targeting NHEJ machinery to overcome platinum resistance in ovarian cancer remain largely unexplored.

ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models.

WEE1 has emerged as an attractive target in epithelial ovarian cancer (EOC), but how EOC cells may alter their sensitivity to WEE1 inhibition remains unclear. Here, through a cell cycle machinery-related gene RNAi screen, we found that targeting outer dense fiber of sperm tails 2-like (ODF2L) was a synthetic lethal partner with WEE1 kinase inhibition in EOC cells. Knockdown of ODF2L robustly sensitized cells to treatment with the WEE1 inhibitor AZD1775 in EOC cell lines in vitro as well as in xenografts in vivo.

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

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.