한빛사 논문
서울대학교병원
Ah-Rong Nama,1, Jeesun Yoonb,1, Mei-Hua Jina, Ju-Hee Banga, Kyoung-Seok Oha, Hye-Rim Seoa,c, Jae-Min Kima,c, Tae-Yong Kima,b, Do-Youn Oha,b,c,*
aCancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
bDepartment of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
cIntegrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea
1Authors contributed equally.
*Corresponding author.
Abstract
Olaparib, a potent PARP inhibitor, has been shown to have great anti-tumor effects in some tumor types. Although biliary tract cancer (BTC) is a good candidate for DNA damage response (DDR)-targeted agents, targeted DDR inhibitors, including olaparib, are currently rarely evaluated in BTC. In our project, a total of ten BTC cell lines were used to assess the efficacy of olaparib. Olaparib alone showed moderate anti-proliferative effects in BTC cells and increased p-ATR and PD-L1 expression levels. In combination with an ATR inhibitor (AZD6738, ceralasertib) showed synergistic anti-proliferative effects and increased DNA strand breaks in vitro. PD-L1 induced by olaparib was also downregulated by ceralasertib through p-STAT-3 and YAP reduction with or without human primary peripheral blood mononuclear cells. In SNU478-xenograft models, the combination treatment significantly suppressed tumor growth. PD-L1 and YAP were strongly downregulated, similar to in vitro conditions, and expression of CXCR2 and CXCR4 was further reduced. In the current ongoing clinical trial (NCT04298021), BTC patients treated with olaparib and ceralasertib combination have shown tumor response. In conclusion, co-targeting of PARP and ATR might be a potential therapeutic approach for patients with BTC.
Keywords : Biliary tract cancer, DNA damage response, PARP, ATR, PD-L1
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