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Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

Departments of ¹ Radiation Oncology and ² Surgery, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Eric J. Bernhard, Department of Radiation Oncology, University of Pennsylvania, 185 John Morgan Building, 37th and Hamilton Walk, Philadelphia, PA 19104-6072. Phone: 215-898-0078; Fax: 215-898-0090; E-mail: bernhard{at}mail.med.upenn.edu.

Activating K-ras mutations are found in 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.

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