Abstract 712: Parf-1A (Partner of ARF isoform 1A) promotes oxaliplatin resistance and is a new prognostic marker of survival in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an incurable malignancy with ineffective treatments and dismal median survival. The INK4a/ARF locus, which encodes the alternative reading frame (ARF) tumor suppressor, is commonly inactivated in PDAC tumors. We recently discovered Parf-1A, a novel “Partner of ARF” whose role in ARF signaling and tumorigenesis is not known. Parf-1A is highly expressed in the normal pancreas and microarray databases suggest Parf expression is altered (both up- and down-regulated) in human PDAC tumors. We generated Parf-1A specific antibodies and examined its protein levels by immunohistochemistry in PDAC tumors from patients who underwent resective surgery. Parf-1A expression was altered in 72% of tumors (33% reduced, 39% elevated) compared to adjacent normal ductal tissue. Tumors with the highest Parf-1A levels were significantly associated with poor patient outcome (median survival 6 months) while patients with undetectable Parf-1A in tumors had a dramatically extended lifespan (median survival 59 months, p=0.0037). Notably, Parf-1A knockdown in cultured PDAC cells increased the p53-independent growth inhibitory activity of ARF. Parf-1A loss also sensitized PDAC cells to oxaliplatin, a chemotherapeutic agent used in combination with gemcitabine to treat PDAC patients. This work identifies Parf-1A as a new inhibitor of ARF p53-independent activity that promotes PDAC chemoresistance in vitro and is a novel prognostic marker of survival in PDAC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 712. doi:1538-7445.AM2012-712