ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Biliary tract cancer (BTC) is a challenging malignancy with limited treatment options.
• DNA damage response (DDR) pathways are implicated in BTC, making them potential therapeutic targets.
• Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, shows anti-tumor activity but is underutilized in BTC.

Purpose of the Study:

• To evaluate the efficacy of olaparib alone and in combination with the ATR inhibitor ceralasertib in biliary tract cancer models.
• To investigate the underlying molecular mechanisms of action for the combination therapy.
• To assess the clinical potential of this combination in an ongoing clinical trial.

Main Methods:

• In vitro assessment of olaparib efficacy across ten BTC cell lines.
• Combination studies with olaparib and ceralasertib (AZD6738) in vitro and in SNU478-xenograft models.
• Analysis of DNA damage markers, PD-L1, p-ATR, p-STAT-3, YAP, CXCR2, and CXCR4 expression.
• Evaluation of patient responses in a clinical trial (NCT04298021).

Main Results:

• Olaparib monotherapy exhibited moderate anti-proliferative effects and increased p-ATR and PD-L1.
• The combination of olaparib and ceralasertib demonstrated synergistic anti-proliferative effects and increased DNA strand breaks in vitro.
• Combination treatment significantly suppressed tumor growth in xenograft models, downregulating PD-L1, YAP, CXCR2, and CXCR4.
• Early clinical data from NCT04298021 indicate tumor response in BTC patients receiving the combination therapy.

Conclusions:

• Co-targeting of PARP and ATR with olaparib and ceralasertib presents a potential therapeutic strategy for biliary tract cancer.
• The combination enhances anti-tumor activity by inducing DNA damage and modulating key signaling pathways.
• Clinical evidence suggests this combination warrants further investigation for BTC treatment.