Abstract 1076: Chemoprevention of pancreatic cancer by targeting Kras mutations for apoptosis.
Authors: Zagorodna Oksana , Huang Shaoyi , Wang Huamin , Wu Xiangwei 
Published: August 2014

Abstract
Pancreatic cancer is often diagnosed at an advanced stage and has a poor prognosis. The overall survival rate is less than 4% at 5 years with most patients dying within one year. Therefore, more effective approaches to treat advanced pancreatic cancer and chemopreventive strategies are in urgent need. Recent reports of early dissemination in pancreatic cancer stress the need for early intervention. Activating mutations of the KRAS oncogene are possibly the single most common genetic abnormality in pancreatic cancer, present in ∼90%-95% of cases. In addition to its role in cancer progression, mutations of the KRAS gene are one of the earliest genetic abnormalities observed in pancreatic cancer, supporting its role as an initiating event for pancreatic cancer formation. Therefore, mutant KRAS gene or its gene product represents an obvious target for the prevention of pancreatic cancer. Unfortunately, direct inhibition of KRAS or its downstream effectors has been largely ineffective in treating pancreatic cancer in clinical trials. The ideas are to find an innovative approach to target KRAS. We recently proposed a new cancer chemoprevention approach SITEP (short-term intermittent therapy to eliminate premalignancy) to target the “drivers” of tumorigenesis to overcome the challenges in cancer chemoprevention. We demonstrated that a two-drug combination of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and a small molecule mimic of the mitochondrial protein Smac /DIABLO (Smac), through a synthetic lethal interaction, specifically targets mutant KRAS expressing premalignant cells for apoptosis without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of Kras-induced lung cancer. In this study, we examined whether targeting KRAS mutant cells for apoptosis in pancreatic precursor lesions (e.g., PanINs) by TRAIL and Smac mimic would be an effective approach for pancreatic cancer chemoprevention. We showed that constitutive expression of mutant KRAS led to the activation of downstream signaling events in the immortalized human pancreatic normal epithelial (HPNE) cells, including phosphorylation of ERK and AKT. TRAIL and Smac mimic treatment showed that control cells are resistant to either TRAIL, or Smac mimic, or TRAIL and Smac mimic combination, and expression of KRAS mutant sensitized cells to the combination of TRAIL and Smac mimic. Short term treatment of Pdx1-Kras mice showed that TRAIL and Smac mimic induced significant apoptosis in abnormal pancreatic ductal cells and reduced number of PanINs. We conclude that targeting oncogenic KRAS signaling pathways in precursor lesions by TRAIL and Smac mimic may prove useful in developing chemoprevention against pancreatic cancer.
Citation Format: Oksana Zagorodna, Shaoyi Huang, Huamin Wang, Xiangwei Wu. Chemoprevention of pancreatic cancer by targeting Kras mutations for apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1076. doi:10.1158/1538-7445.AM2013-1076