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

Abstract

Activating K-ras mutations are found in f90% 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. (Cancer Res 2005; 65(18): 8433-41)

Hdm2 is regulated by K-Ras and mediates p53-independent functions in pancreatic cancer cells

“…p53 also appeared to be overexpressed in the same pancreatic cancer cells as hdm2. This was probably because the cancer cells, unlike HPDE-E6E7 cells (Ouyang et al, 2000), contain mutant p53 (Brunner et al, 2005; Panc-28 cells, data not shown), which tends to be more stable than the wild-type protein (Jackson et al, 2003). The expression of hdm2 in cell lines other than HPDE-E6E7 and Panc-1 cells appeared mostly constitutive and independent of serum factors ( Figure 1a).…”

Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts

“…Apart from promoting cell growth, several signalling pathways diverge downstream from activated PKB/Akt that suppresses apoptosis. The enhancement of cell survival by PI3K signalling probably has a major function during early cancer development, and has also been linked to the high levels drug and radiation resistance seen in patients with pancreatic cancer (Ng et al, 2001;Bondar et al, 2002;Mackenzie, 2004;Brunner et al, 2005), although it should be noted that pancreatic cancers are heterogeneous, and the activation of additional signalling elements, including Stat3, NFkB, and hedgehog pathway, is also likely to be an important determinant of biological aggression (Bardeesy and DePinho, 2002; Arlt et al, Thayer et al, 2003). Experimental PI3K inhibitors can sensitise resistant cancer cells to cytotoxic agents or radiation, suggesting therapeutic potential in the clinic, but until recently in vivo testing was limited due to their toxicity or poor pharmacological properties.…”

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

“…KRAS downregulation using siRNA is growth inhibitory in KRASmutant cells with little to no effect in KRAS wild-type counterparts highlighting the dependency of KRASmutant cells on KRAS activity for survival, proliferation, and tumorigenicitiy (26,27). Furthermore, downregulation of mutant KRAS has been shown to potentiate responses to other drugs (27,33). Methotrexate has also been implicated in the inhibition of isoprenylcysteine carboxyl methyltransferase, an enzyme necessary for KRAS membrane localization and activation.…”