p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer.

Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRAS G12D -driven PC tumorigenesis. iASPP suppresses PC onset driven by KRAS G12D alone or KRAS G12D in combination with mutant p53 R172H . iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRAS G12D -induced ADM, pancreatitis and PC tumorigenesis in vivo. KRAS G12D /iASPP Δ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRAS G12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.