Abstract B19: The ATR inhibitor, AZD6738, synergizes with other DNA damage response inhibitors and genotoxic drugs in pancreatic ductal adenocarcinoma cell lines: Opportunities for new therapeutic combinations

Mutations in oncogenes, tumor suppressor and DNA damage response (DDR) mediator genes drive or permit malignant transformation but also increase endogenous replication stress. The serine/threonine kinase ATR plays a critical role in safeguarding genome integrity from such replication stress and several studies have demonstrated the increased reliance of cancer cells on ATR function. We investigated the therapeutic opportunities for the ATR inhibitor, AZD6738, in combination with DNA damaging or DDR-targeted agents, in the context of pancreatic ductal adenocarcinoma (PDAC).We evaluated four DNA-damaging agents (gemcitabine, 5-fluorouracil, oxaliplatin, SN38 (the active metabolite of irinotecan)) and three DDR-targeted agents (Wee1 inhibitor (AZD1775), Chk1 inhibitor (MK8776), PARP inhibitor (AZD2281)), each in combination with AZD6738 at multiple concentrations. Efficacy of these combinations was tested in growth inhibition assays in vitro, using a panel of cell lines in order to capture some of the genetic heterogeneity observed in PDAC: two human cell lines and four lines from the KrasG12D; Trp53R172H; Pdx-Cre (KPC) mouse. Synergistic growth inhibition was identified applying both Bliss Independence and Loewe models, using Combenefit software. All the KPC mouse cell lines were sensitive to AZD6738 as a single agent, with GI50 ranging from 346 to 566 nM. MIA PaCa-2 were sensitive to AZD6738, achieving >90% growth inhibition, with GI50 of 2.2 μM. PANC-1 cells were less s...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapies Targeting Checkpoints and Mismatch Repair: Poster Presentations - Proffered Abstracts Source Type: research