Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras?

Abstract

1. SummaryThe high prevalence of mutated ras genes inhuman cancers makes them an attractive target fordrug design. A promising method of interfering inRas function involves inhibiting the enzyme farnesyl-transferase FTase , which modifies Ras and other.proteins with the farnesyl isoprenoid lipid that isrequired for their correct cellular localization andbiological activity. FTase inhibitors, or FTIs, havedemonstrated the potent and specific ability to blockRas processing, signaling and transformation in trans-formed and tumor cell lines both in vitro and inanimal models. During the development of FTIs aspharmaceutical agents for clinical use, several intrigu-ing questions about their activity have arisen. Forexample, despite the requirement for intact Ras func-tion for normal cell growth, FTIs have turned out tobe surprisingly nontoxic to normal cells. In addition,K-Ras, the most commonly mutated form of Ras inhuman cancers, is far more resistant to FTI actionthan H-Ras. Nevertheless, FTIs show potent activityin reducing the tumorigenicity of some human tumorcell lines containing activated K-Ras mutants. Indeed,a simple determination of the ras mutation status of agiven tumor is not a predictor of the ability of FTIs toinhibit its growth. These findings have led to thelikelihood that inhibition of mutated Ras proteinfunction is not the sole means by which FTIs evoketheir anti-tumor activity. Thus, in addition to thenecessary improvements in pharmacokinetics of leadcompounds required to bring drugs to clinic, a con-siderable amount of attention is now being devoted toattempts to understand the mechanism of biologicalaction of FTIs. What are the biological consequencesof the recently discovered ability of K-Ras4B toserve as a substrate for geranylgeranyltransferase.GGTase I in addition to FTase? In addition toinhibition of Ras processing, what other farnesylatedproteins are affected? How important are these otherproteins in the final determination of FTI responsive-ness? What can be done to optimize the efficacy ofFTIs? This review will summarize our current under-standing of the biological consequences of FTI treat-ment of normal and transformed cells, and presentour own speculations as to where future researchefforts in these areas might usefully be directed.2. IntroductionSince 1982, when mutated ras genes were firstdetected in human cancers, extensive research studieshave determined the function of Ras proteins andhave established an important contribution of aber-rant Ras function to human carcinogenesis. Conse-quently, there is considerable interest in the develop-ment of inhibitors of Ras function for use in cancertreatment. In particular, significant progress has beenmade in the development of farnesyltransferase in-hibitors as potential anti-Ras drugs. While there issignificant evidence to support the anti-tumor actionof these inhibitors, much remains to be understoodabout how these inhibitors may target Ras functionand how effective they will be for cancer treatment.This review will provide an assessment of the currentstatus of these efforts.3. The role of aberrant Ras function in humancarcinogenesisMutated versions of the three human ras geneshave been detected in 30% of all human cancers,implying an important role for aberrant Ras functionin carcinogenesis 1–3 . The frequency is not uniformwxwith respect to tumor type, suggesting that ras muta-tions contribute to the development of some, but notall, tumors. For example, ras mutations are highlyprevalent in pancreatic 90% , lung 40% and col-. .orectal 50% carcinomas. Thus, aberrant Ras func-.tion is believed to contribute to the development of atleast a major subset of these neoplasms. In contrast,mutated ras genes are rarely associated with thedevelopment of breast, ovarian and cervical carcino-mas .)5% . Therefore, aberrant Ras function maynot be important in promoting or maintaining themalignant and invasive properties of these tumors.Alternatively, since Ras proteins are regulators ofdiverse extracellular signaling pathways that regulatecell growth, differentiation and apoptosis 4,5 , thewxderegulated function of other cellular components cancause aberrant Ras function in the absence of muta-tions in Ras itself 6 . For example, overexpression ofwxthe HER2rNeurErbB2 or epidermal growth factor