Abstract 331: Therapeutic co-targeting of WEE1 and ATM has synergistic effects and contributes to downregulation of PD-L1 expression in pancreatic cancer

Abstract

Abstract Background: Currently, targeting DNA damage response (DDR) is one of strategies for new cancer drug development. DDR pathway involves DNA damage repair, cell cycle progression, apoptosis, and regulate the immune system. In pancreatic cancer (PC), one of the most fatal disease, TP53 mutation was found in approximately 78% of cases and BRCA pathway alteration including BRCA1, BRCA2, the ataxia telangiectasia mutated (ATM) and PALB2 was observed in 5% (germline) and 12% (somatic) of patients. The purpose of this study is to evaluate the DDR-targeting strategy using Wee1 inhibitor and ATM inhibitor in PC. Methods: Using a total of 11 kinds of PC cell lines (AsPC-1, Capan-1, Capan-2, MIA PaCa-2, PANC-1, SNU213, SNU324, SNU410, SNU2822, SNU2913, and SNU2918), AZD1775 (Wee1 inhibitor) and AZD0156 (ATM inhibitor) were tested. Results: AZD1775 significantly inhibited cell proliferation in all of the PC cell lines. AZD1775 monotherapy induced apoptosis and S phase arrest, and decreased Wee1/ p-wee1/ p-CDC2 expression. An increase of rH2AX and caspase-7 cleavage were occurred by AZD1775. When the cells were treated with AZD1775, upregulation of p-ATM was observed. The combination of AZD1775 and AZD0156, the synergism was found. P-wee1 and p-CDC2 were downregulated more obviously in co-treated cells compared with monotherapy. In some cells, PD-L1 was increased after AZD1775 treatment. Interestingly the combination of AZD1775 and AZD0156 synergistically reduced PD-L1 protein level in the cancer cells, especially in SNU213 and SNU2913 cells. Conclusion: Therapeutic WEE1 and ATM co-targeting strategy demonstrated promising anti-cancer effect in pancreatic cancer cells. Moreover, this co-treatment blocked PD-L1 expression. Taken together, this supports further clinical development of DDR targeting strategy in pancreatic cancer. Citation Format: Meihua Jin, Ah-Rong Nam, Ji Eun Park, Ju Hee Bang, Yung-Jue Bang, Do-Youn Oh. Therapeutic co-targeting of WEE1 and ATM has synergistic effects and contributes to downregulation of PD-L1 expression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 331.