Abstract B55: Chemoprevention of pancreatic cancer by targeting Kras mutations for apoptosis

Pancreatic cancer is often diagnosed at an advanced stage and has a poor prognosis. The 5-year survival rate is less than 5% 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 one of the most common genetic abnormalities 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. 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. Control cells are resistant to either TRAIL, or Smac mimic, or TRAIL and Smac mimic combination. The expression of Kras mutant sensitized HPNE cells to the combination of TRAIL and Smac mimic. Short term treatment of Pdx1-Cre, LSL-KrasG12D mice showed that TRAIL and Smac mimic induced significant apoptosis in abnormal pancreatic ductal cells and reduced number of PanINs. Similar short-term and intermittent treatment studies are ongoing in Pdx1-Cre, LSL-KrasG12D, LSL-p53 mouse model. 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, Huamin Wang, Xiangwei Wu. Chemoprevention of pancreatic cancer by targeting Kras mutations for apoptosis. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B55.