DGKA Provides Platinum Resistance in Ovarian Cancer Through Activation of c-JUN–WEE1 Signaling

Abstract

Purpose: Although platinum compounds are the first-line treatment for ovarian cancer, the majority of patients relapse and develop resistance to treatment. However, the mechanism underlying resistance is unclear. The goal of our study is to decipher the mechanism by which a metabolic kinase, diacylglycerol kinase alpha (DGKA), confers platinum resistance in ovarian cancer.Experimental Design: Metabolic kinase RNAi synthetic lethal screening was used to identify a cisplatin resistance driver in ovarian cancer. DGKA variants were used to demonstrate the need for DGKA activity in cisplatin resistance. Phospho-proteomic and genomic screens were performed to identify downstream effectors of DGKA. Therapeutic efficacy of targeting DGKA was confirmed and clinical relevance of DGKA signaling was validated using ovarian cancer patient-derived tumors that had different responses to platinum-based therapy.Results: We found that platinum resistance was mediated by DGKA and its product, phosphatidic acid (PA), in ovarian cancer. Proteomic and genomic screens revealed that DGKA activates the transcription factor c-JUN and consequently enhances expression of a cell-cycle regulator, WEE1. Mechanistically, PA facilitates c-JUN N-terminal kinase recruitment to c-JUN and its nuclear localization, leading to c-JUN activation upon cisplatin exposure. Pharmacologic inhibition of DGKA sensitized ovarian cancer cells to cisplatin treatment and DGKA-c-JUN-WEE1 signaling positively correlated with platinum resistance in tumors derived from patients with ovarian cancer.Conclusions: Our study demonstrates how the DGKA-derived lipid messenger, PA, contributes to cisplatin resistance by intertwining with kinase and transcription networks, and provides preclinical evidence for targeting DGKA as a new strategy in ovarian cancer treatment to battle cisplatin resistance.

A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer

“…In the same line, POLE gene damaging variants ( 129 ) and TP53 mutation ( 130 ) may also be correlated with the immunotherapeutic effect, this suggests that the combination of immune checkpoint inhibitor and certain pathway-targeted drugs may be a future direction for stratified therapy of EOVC patients. Besides, it’s reported that the DGKA-c-JUN-WEE1 signal pathway participates in the mechanism of platinum resistance in EOC patients ( 131 ), providing direction for targeted therapy to antagonize platinum resistance in the future study. Compared with effective but poorly tolerated concurrent therapy, Fang et al.…”

Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer

“…Recent studies have shown that WEE1 is implicated in multidrug resistance, particularly to drugs related to cell cycle modulators, DNA‐damaging agents, or DNA‐repair inhibitors. Consistently, the drug resistance of tumors is associated with increased expression of WEE1 or activation of WEE1 signaling pathways 11,20 . Indeed, several reports have shown the synergistic effect of the WEE1 inhibitor with various anticancer agents in a variety of malignant diseases, such as the AURKA inhibitor alisertib (MLN8237) in HNSCC, 14 an ATR inhibitor in diffuse large B‐cell lymphoma, 15 a BET inhibitor in non‐small‐cell lung cancer, 35 trastuzumab in HER2‐positive breast cancer, 36 and avapritinib in gastrointestinal stromal tumors 20 .…”

“…Several reports have shown that the differential antitumor activity of the WEE1 inhibitor appears to be particularly dependent on TP53 mutation status 9‐11,14 . Given that TP53 is the most frequently altered gene in UC 18,19 and CDDP is the flagship drug for advanced UC, a synergistic antitumor effect of MK‐1775 and CDDP can be expected.…”

LNC00115 Mediates Cisplatin Resistance by Regulating the miR-7/ERK Signalling Pathway in Ovarian Cancer

“…However, approximately 70% of ovarian cancer patients relapse after receiving cisplatin chemotherapy, 21 and the mechanism of cisplatin resistance in ovarian cancer is not clear. 22 In this study, we determined for the first time that LNC00115 is involved in the regulation of cisplatin resistance in ovarian cancer. Compared with that in the ovarian cancer cell line SKOV3, LNC00115 was more highly expressed in the ovarian cancer cisplatin-resistant cell line SKOV3-DDP.…”