In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 323-323
Abstract:
Background: Currently, targeting DNA damage response (DDR) is one strategy for new cancer drug development. DDR pathway involves DNA damage repair, cell cycle progression, apoptosis, and regulate the immune system. Biliary tract cancer (BTC) has a poor prognosis with a huge unmet medical need. In BTC, DNA repair pathway, which includes BAP1, MSH6, BRCA1, ATM, MLH1, and MSH2, is altered in about 20 % of cases. TP53 module is observed in 33.9% of cases (Nat Genet 2015). The purpose of this study is to evaluate DNA damage response (DDR)-targeting strategy in BTC. Methods: Using 10 kinds of BTC cell lines (SNU245, SNU308, SNU478, SNU869, SNU1079, SNU1196, HuCCT-1, TFK-1, SNU2670, and SNU2773). AZD1775 (Wee1 inhibitor), AZD6738 (ATR inhibitor) and AZD0156 (ATM inhibitor) were tested. Results: Among 10 cell lines, SNU308 and HuCCT1 were very sensitive to AZD1775, and SNU2670 and SNU2773 were relatively resistant to AZD1775. AZD1775 blocked phosphorylation of CDK1 (Y15) and CDK2 (Y15) in sensitive cells and but increased rH2AX in all cells. AZD1775 significantly increased apoptosis (cleavage of PARP and caspase-7) and G2/M arrest. Interestingly, Wee1 inhibitor increased pATR and pATM levels in resistant cells. AZD1775 in combination with AZD6738 or AZD0156 showed more potent antitumor effect than monotherapy of each drug. Conclusion: Inhibition of Wee1 has an antitumor effect in some BTC cells. In combination with ATM/ATR inhibitors, the resistance to Wee1 inhibition could be overcome. Taken together, this study supports the further clinical development of DDR-targeting strategy in BTC as monotherapy or in combination. Citation Format: Ah Rong Nam, Ji Eun Park, Ju-Hee Bang, Mei Hua Jin, Yung-Jue Bang, Do-Youn Oh. DNA damage response (DDR)-targeting strategy by targeting WEE1 and or ATM/ATR works in biliary tract 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 323.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-323
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink