Oncogenic K-Ras signals through epidermal growth factor receptor and wild-type H-Ras to promote radiation survival in pancreatic and colorectal carcinoma cells.

Pancreatic and colorectal carcinomas frequently express oncogenic/mutant K-Ras that contributes to both tumorigenesis and clinically observed resistance to radiation treatment. We have previously shown that farnesyltransferase inhibitors (FTI) radiosensitize many pancreatic and colorectal cancer cell lines that express oncogenic K-ras at doses that inhibit the prenylation and activation of H-Ras but not K-Ras. In the present study, we have examined the mechanism of FTI-mediated radiosensitization in cell lines that express oncogenic K-Ras and found that wild-type H-Ras is a contributor to radiation survival in tumor cells that express oncogenic K-Ras. In these experiments, inhibiting the expression of oncogenic K-Ras, wild-type H-Ras, or epidermal growth factor receptor (EGFR) led to similar levels of radiosensitization as treatment with the FTI tipifarnib. Treatment with the EGFR inhibitor gefitinib led to similar levels of radiosensitization, and the combinations of tipifarnib or gefitinib plus inhibition of K-Ras, H-Ras, or EGFR expression did not provide additional radiosensitization compared with tipifarnib or gefitinib alone. Finally, supplementing culture medium with the EGFR ligand transforming growth factor alpha was able to reverse the radiosensitizing effect of inhibiting K-ras expression. Taken together, these findings suggest that EGFR-activated H-Ras signaling is initiated by oncogenic K-Ras to promote radiation survival in pancreatic and colorectal cancers

ORIGINAL ARTICLE Adenosquamous Versus Adenocarcinoma of the Pancreas: A Population-Based Outcomes Analysis

# The Author(s) 2010. This article is published with open access at Springerlink.com Background Pancreatic adenosquamous carcinoma has historically been characterized as having a more aggressive clinical course than ductal adenocarcinoma. The natural history of this disease, however, is essentially unknown. Methods We evaluated the clinical characteristics of all patients with pancreatic adenosquamous carcinoma recorded in the California Cancer Registry 2000–2007 and compared them to those of patients with ductal adenocarcinoma. Results Ninety-five patients with pancreatic adenosquamous carcinoma and 14,746 patients with ductal adenocarcinoma were identified. Demographics were similar between subtypes (p>0.05). Disease stage at presentation was also similar; over 50 % of each diagnostic group presented with metastatic disease (p=0.62). Surgical resection was more common among patients with locoregional adenosquamous carcinoma than adenocarcinoma (p=0.0004), but rates of adjuvant therapy administration were similar (p>0.05). The cohorts ’ median overall survival durations were similar in a Cox proportional hazards model (p=0.45); overall survival was also similar when only patients with resected disease were considered (p= 0.65). Early stage, resection and receipt of radiation or chemotherapy were favorable independent prognostic factors among patients with adenosquamous carcinoma. The median overall survival duration of patients with resected adenosquamous carcinoma was 12 months (95 % CI, 8–52)