Activating K-ras mutations are found in approximately 90% of pancreatic 
carcinomas and may contribute to the poor prognosis of these tumors. Because 
radiotherapy is frequently used in pancreatic cancer treatment, we assessed the 
contribution of oncogenic K-ras signaling to pancreatic cancer radiosensitivity. 
Seven human pancreatic carcinoma lines with activated K-ras and two cell lines 
with wild-type ras were used to examine clonogenic cell survival after Ras 
inhibition. Ras inhibition was accomplished by small interfering RNA (siRNA) 
knockdown of K-ras expression and by blocking Ras processing using a panel of 
prenyltransferase inhibitors of differing specificity for the two 
prenyltransferases that modify K-Ras. K-ras knockdown by siRNA or inhibition of 
prenyltransferase activity resulted in radiation sensitization in vitro and in 
vivo in tumors with oncogenic K-ras mutations. Inhibition of farnesyltransferase 
alone was sufficient to radiosensitize most K-ras mutant tumors, although K-Ras 
prenylation was not blocked. These results show that inhibition of activated 
K-Ras can promote radiation killing of pancreatic carcinoma in a superadditive 
manner. The finding that farnesyltransferase inhibition alone radiosensitizes 
tumors with K-ras mutations implies that a farnesyltransferase 
inhibitor-sensitive protein other than K-Ras may contribute to survival in the 
context of mutant K-ras. Farnesyltransferase inhibitors could therefore be of 
use as sensitizers for pancreatic carcinoma radiotherapy.