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Actionable perturbations in the DNA damage response establish synergistic therapeutic routes in ATM deficient pancreatic cancer
13 August 2018 (online)
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-associated death in the Western World. PDAC bears a high accumulation of oncogenic mutations. Recent sequencing studies found Ataxia-Telangiectasia Mutated (ATM) frequently mutated in PDAC. Our lab previously showed that the loss of ATM accelerates EMT and promotes genomic instability (Russell, Nature communication, 2013; Perkhofer, 2017, Cancer Research). In line with the altered genomic integrity of ATM-mutated PDAC established genotype specific strategies like PARP- and ATR- inhibition. However, these treatment strategies tended to show early resistance and particularly ATR inhibition renders toxicity at least in humans (Perkhofer, 2017, Cancer Research). Here, we unravel novel synergistic routes based on actionable perturbations in the DNA damage response (i) to overcome chemoresistance and (ii) to present a genotype tailored cocktail of targeted therapies for ATM-mutated PDAC. Based on the Atmfl/fl; Kras+/G12D; Ptf1a+/Cre (AKC) and Kras+/G12D; Ptf1a+/Cre (KC) mouse model primary AKC and KC PDAC cell lines were established. First, we screened a set of inhibitors and chemotherapeutics for single agent efficiency using conventional MTT assyas. Second, the PreCISE (predictor of chemical inhibitor synergistic effects) software tool was applied to unravel synergy in actionable perturbations of the DNA damage response. Thereby, systematic combinational screening efforts found synergy between inhibition of the DNA-PKC, ATR and PARP signaling leading to synthetic lethality in AKC cell lines. Triple pathway inhibition was then combined with conventional topoisomerase inhibitors, the latter having shown substantially higher activity in AKC lines in our single agent screen. Systematic characterization of the DDR in such treated cell lines provided a coherent understanding of the molecular mechanism behind and key observations were validated in orthotopic and subcutaneous transplantation studies. Summarized, based on a novel genomic unstable, ATM-depleted PDAC model, we could identify new targeted and synergistic routes to reach highest efficiency with lowest toxicity to pave the way to clinical trials in this subgroup of PDAC patients.