Precision medicine meets the DNA damage response in pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the major cancer problems in the present but even more in the future. Today, over 7% of all cancer deaths in the USA are PDAC caused and the incidence is predicted to increase further over the next decade (reviewed in [1]). The step wise progression from ductal metaplasia (ADM) via acinar to ductal reprogramming steps (ADR) to pancreatic intraepithelial neoplasia (PanIN) and finally frank PDAC is orchestrated through an interplay of various mutations. Recent genome sequencing studies have shed light on the mutational landscape of PDAC including a small set of key driver mutations like KRAS, TP53, CDKN2A, or SMAD4 guided by a high number of passenger mutations. Thereby, the latter establish the characteristic intra- and intertumoral heterogeneity [2] but also allows for the first time practical PDAC subtyping. Here, the so-called “unstable PDAC” subtype comprises a relevant and maybe best druggable new entity [3]. Typically, the unstable PDAC subtype harbours mutations in genes involved in DNA damage response (DDR) such as BRCA1/2, PALPB2 and ATM [2], which are associated with increased chemoresistance, aggressive disease course and thus dismal prognosis. Specifically, BRCA1/2-mutations in PDAC seem to generate a tumour biology being more sensitive to platinum-based chemotherapies and PARP inhibition [3]. However, genotype-tailored therapies for non-BRCA1/2-mutated unstable PDACs, such as mutations in the serine/threonine protein kinase Ataxia-telangiectasia-mutated (ATM), remain to be identified