Perspectives on farnesyl transferase inhibitors in cancer therapy

Cancer Letters 206 (2004) 159–167 www.elsevier.com/locate/canlet

Perspectives on farnesyl transferase inhibitors in cancer therapy Julien Mazieres, Anne Pradines, Gilles Favre* De´partement Innovation The´rapeutique et Oncologie Mole´culaire, INSERM U563, Institut Claudius Regaud, 20-24, rue du pont Saint-Pierre, Toulouse cedex 31052, France Received 29 July 2003; accepted 5 August 2003

Abstract The discovery that the transforming activity of oncogenic Ras depends upon its post-translational farnesylation has led to the development of farnesyl transferase inhibitors (FTIs). FTIs inhibit the growth of ras-transformed cells in vitro and induce tumor regression in Ras-dependent tumors. Currently, FTIs are undergoing clinical trials in various solid or hematological malignancies. In this review, we will summarize our current knowledge on cellular effect and molecular mechanism of FTIs. We will then describe recent clinical trials and propose some clues for their interpretation. Based on pre-clinical findings, we will emphasize on the optimal use of FTIs in anti-cancer strategy and lastly, we will insist on the interest of combining FTIs with chemotherapy, radiotherapy or other targeted agents. q 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Farnesyl transferase inhibitors; Ras; Rho; Cell cycle; Apoptosis; Clinical trials; Chemotherapy; Cancer therapy

1. Introduction Our better understanding of cell biology and cancer genetics has permitted identification of novel targets within tumor cells that lead to the development of rational mechanism-based drugs. Farnesyl transferase inhibitors (FTIs) are one of the first and of the most well-studied oncogene-targeted therapy. These agents were conceived to prevent the function of Ras proteins by blocking the post-translational attachment of prenyl-moiety to its C-terminal cysteine, thereby inhibiting its membrane localization and function. A lot of hope and enthusiasm have accompanied the development of such agents because Ras is a key * Corresponding author. Tel.: þ 33-56142-42-23; fax: þ 3356142-46-31. E-mail address: [email protected] (G. Favre).

protein in tumorigenesis and is found mutated in approximately 30% of all human cancers. After encouraging pre-clinical results, FTIs are currently in clinical development. In this review we will focus on the mechanisms of action of FTI that appear to be more complex than previously expected. Indeed, there is still a lot to learn about the biological substratum of their anti-cancer action and their real target(s).

2. Pharmacological effects of FTIs 2.1. Protein prenylation: a post-translational modification required for biological functions of many proteins Prenylation is the covalent addition of an isoprenoid moiety, farnesyl or geranylgeranyl, issued

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from the cholesterol biosynthetic pathway to carboxyterminal cysteine of substrate proteins [1]. Approximately 0.5– 1% of cellular protein are isoprenylated, notably small GTPases of the Ras superfamily. Prenylation is required for their proper cellular localization and biological functions. Prenylation is catalyzed either by farnesyltransferase (FTase) or geranylgeranyltransferase I (GGTase I) [1] and occurs on the cysteine in a CAAX consensus sequence (A is aliphatic and X is any amino acid). The terminal X residue of the CAAX motif determines whether farnesylation or geranylgeranylation occurs: GGTase I prefers as substrate proteins where X is leucine as for RhoA, whereas FTase prefers X to be methionine, serine or glutamine as for Ras proteins [2]. Nevertheless substrate specificity with FTase is not absolute [3]. Thus GGTase I can modify Ki-Ras or N-Ras when FTase is inhibited [4]. Moreover, we and others demonstrated that the small GTPase RhoB can be either farnesylated or geranylgeranylated while X is leucine [5,6]. After prenylation, proteins undergo subsequent biochemical processes involving proteolytic cleavage of the AAX peptide, carboxymethylation of the farnesylated cysteine residue, and lastly for some proteins, attachment of a fatty acid palmitate residue near the prenylated cysteine. 2.2. Inhibitors of farnesyl-transferase The finding that the farnesylation of Ras is an obligatory step for its transforming activity made FTase a very attractive target for anti-cancer drug design. Several strategies were used to develop FTase inhibitors: screening of natural and chemical libraries, chemical rational design of farnesyl pyrophosphate (FPP) analogues or CAAX peptidomimetics (for review, see Ref. [7]). To summarize, FTIs fall into four main classes: (1) FPP analogues that compete with the substrate FPP for FT such as hydroxyfarnesyl phosphonic acid; (2) CAAX peptidomimetics that compete with the CAAX box of Ras for FT, such as FTI-277 or L-774,832; (3) the bisubstrate inhibitors that combine the properties of a farnesyl diphosphate analogue together with a peptidomimetic, such as BMS-186511 and (4) compounds discovered by throughput screening of libraries such as SCH66336 and R115777.

2.3. Several critical cellular effects are modulated by FTIs Several reports have shown that FTIs inhibit the malignant growth in a wide variety of murine and human tumor cell lines. FTIs inhibit the anchorageindependent growth of H-ras transformed rodent fibroblasts while less efficient on transformed cells either by raf or mos [8,9] or by a geranylgeranylated Ras [10 – 12] indicating a specific effect of FTIs on Ras signaling pathways [9,11]. FTIs also inhibit anchorage-independent growth of many human cancer cell lines independently of the histological type or ras mutation status. For example, the FTI L-744,832 inhibits the anchorage-dependent and -independent growth of 70% of 42 human cell lines. [13]. The FTIs, such as FTI-277, interrupt the Raf/ MEKK/MAPK kinase cascade activation in H-Ras and K-Ras transformed cells without effect in cells transformed with a geranylgeranylated mutant of Ras [11,12,14]. Moreover FTIs inhibit PI3 kinase pathways with an inhibition of AKT [15] and of p70S6 kinase phosphorylation [16,17]. The FTIs are potent modulators of cell cycle. In human tumour cell lines, FTIs induce accumulation of G0/G1 or G2/M phase cells or have no effect on cell cycle distribution depending on the cell line [18 – 21]. The G0/G1 blockade is often correlated with a p53-dependent p21waf/cip1 induction in many cell types [21] but FTIs still induce G0/G1 cell cycle arrest in cell expressing the p53 inhibitory protein HPV16 E6 or lacking the p21waf1/cip1 gene [22]. The ability of FTIs to induce accumulation of G2/M phase cells correlate with an up-regulation of the cyclindependent kinase inhibitor p27Kip1 and of Bcl-2 protein in liver cancer cell lines [23]. Moreover Crespo et al. have demonstrated that FTI-2153 prevents the progression from prophase to metaphase, by inhibiting the formation of bipolar spindle [24] independently of Ras or p53 mutation status [25]. Another important effect of FTIs is the induction of apoptosis in several cell lines and in nude mice bearing human carcinoma [26,27] notably under specific conditions such as low serum concentration or lack of substratum attachment [26,28] suggesting that induction of apoptosis by FTIs requires a second death-promoting signal. Several reports showed that FTIs induce apoptosis through the release of

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The most convincing results for FTI as candidates as anti-cancer drugs are their capacity to inhibit tumor growth in vivo. Many studies showed the efficacy of FTI to inhibit the growth of rastransformed fibroblasts as well as human tumor xenografts in a dose-dependent manner [16,32]. Lantry et al. [33] demonstrated that FTIs can inhibit chemically induced lung tumor with K-Ras mutations in immunocompetent mice. FTIs have also been tested in transgenic mice bearing the oncogene H-ras under the control of the mouse mammary tumor virus (MMTV) tissue-specific promoter. These mice develop spontaneously mammary and salivary tumors and treatment with FTIs induces dramatic regression of tumors to undetectable levels whereas no tumor regression is observed in transgenic mice that express oncogenic K-ras [34]. Other convincing results have been obtained from mice harboring multiple genetic alterations. FTIs induce tumor regression in H-ras/c-myc mice as well as in oncogenic H-Ras transgenic mice that lack p53 [31]. In addition to their anti-tumor efficacy in animals models, FTIs lack toxicity arguing for a high therapeutic index [16,34]. While it was demonstrated that FTIs display a cytostatic effect [16], impressive tumor regression was observed in transgenic mice suggesting that FTIs might also exert a cytotoxic effect in tumor cells [30,31].

the anti-neoplastic effects of FTIs not only correlate with their effect on Ras isoprenylation. In fact, FTIs can inhibit malignant growth induced by activated K-Ras or N-Ras even though both of them have been shown to undergo geranylgeranylation and potentially remain functional [35]. Moreover, the kinetics of phenotypic reversion in ras-transformed Rat1 cells is faster than the kinetics of ras-farnesylation inhibition (H-Ras half-life is about 24 h) [36]. As FTIs induce multiple effects on cancer cells, we can logically hypothesize that not one but several farnesylated proteins are involved in these effects. Characterization of such proteins is of high interest because it will allow identification of new targets or signaling pathways involved in carcinogenesis. RhoB has come into sight as a key target of FTIs. Because of its particular CAAX box, RhoB can be either farnesylated or geranylgeranylated [5,6]. Following several observations, Prendergast et al. put forward the RhoB/FTI hypothesis, suggesting that the anti-tumor effects of FTIs depend on the accumulation of the geranylgeranylated form of RhoB [6,37,38]. However with CAAX mutants of RhoB that result either in exclusively farnesylated or exclusively geranylgeranylated RhoB [5] we observed in human cancer cells that RhoB-F was just as potent as RhoBGG at inhibiting oncogenic signaling and tumor survival pathways, inducing apoptosis and suppressing tumor growth in cell culture and in nude mice arguing that RhoB-GG and RhoB-F displayed the same role in suppressing tumor [39]. Besides RhoB, many other proteins that are farnesylated belonging to small G protein family (RhoD, Rnd3, TC10, Rheb or Rap2A) or not such as CENP-E, CENP-F, PTPCAAX 1 or 2 have been proposed as putative targets for FTIs (reviewed in Ref. [21]). To summarize, it seems that the effects of FTI involve the inhibition of many farnesylated proteins rather than of a single target. Therefore the quest of the FTIs targets still represents an important challenge.

3. FTIs target(s)

4. FTIs in clinical trials

Although FTIs were originally conceived to target mutant or aberrant Ras function in cancer, recent findings argue that the mechanism of action of FTIs is not as simple as originally envisioned and that

4.1. Results of main clinical trials

cytochrome c from the mitochondria resulting in caspase-3 activation [21,27]. Likewise, simultaneous treatment of H-Ras transformed fibroblasts with a MEK1,2 inhibitor markedly enhances caspase-3 activity and the apoptotic response to SCH66336 [29]. In two reports, the tumor regression observed after FTI treatment in transgenic mice was correlated with an increase of apoptosis in the tumor cells [30,31] regardless of the p53 status [31]. 2.4. FTIs display in vivo impressive activity

It took only 5 years from 1993, when the first FTI were described, to 1998 when results from the first

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phase I studies were reported. Four FTIs have entered clinical development: R115777 (Zarnestraq), SCH-66336 (Sarasarq), L-778,123 and BMS-214662. More than 20 phases I and a few phases II and III studies have been published or reported in recent oncology meetings with FTI as single agent as well as in combination with standard chemotherapy. R115777 and BMS-214662 are given orally with different schedules whereas the two other agents are administrated intravenously. Dose-limiting toxicities have included myelosuppression, gastrointestinal disorders, peripheral neuropathy and fatigue. Because of cardiac conduction abnormalities (QTc prolongation), the clinical development of L-778,123 has been discontinued. Some unexpected responses have been reported in patients with heavily pre-treated lung, pancreatic or gastrointestinal cancers (details in Refs. [40,41]). The first phase II study of an FTI was conducted in breast cancer and shows interesting rate of partial response and stable disease [42]. Other trials have been conducted in patients with hematological malignancies and attractive results have recently been reported in myelofibrosis and chronic myeloid leukemia [43]. Some promising results have also been described in recurrent malignant glioma [44]. A phase III study has been conducted in patients with advanced refractory colorectal cancer who had failed two prior chemotherapy regimens. Unfortunately, median survival was comparable if R1115777 (Zarnestraw) or placebo was administered [45].

to MTD, using higher dose is useless and could even lead to a loss of effectiveness. Thus, a threshold ‘biologically effective dose’ will be more accurate. Selection of appropriate endpoints in phase II or III is also subject to controversies. As FTIs are considered as cytostatic agents, median survival, 5-year survival or analysis of quality of life are probably better end points than response rate. The measurement of surrogate biomarkers has been used to study the biological activity of FTIs. In a recent study, Adjei et al. [46] propose unprocessed chaperone protein HDJ-2 and prelamin A as suitable markers of FT inhibition in clinical samples. Identification and use of relevant markers will allow to determine the lowest biologically effective dose which permits a long-term maintenance therapy with FTIs and to evaluate their efficacity more accurately. In clinical trials, FTIs are evaluated most of the time in metastatic or advanced tumors although it appears from pre-clinical studies that FTIs may be most effective against tumors that retain apoptotic capacity [47]. Their low toxicity and their cytostatic effect favor their use as adjuvant treatment after surgery or induction chemotherapy in order to prevent tumoral repopulation. They should thus be studied extensively in such strategy.

4.2. Teaching from clinical trials with FTIs

FTIs as single agents appear to have modest and inconstant anti-neoplastic effects. We have emphasized previously the fact that FTIs effects cannot be restricted to an inhibition of oncogenic Ras but rather target numerous proteins and signaling pathways. FTIs affect actin cytoskeleton, cell morphology, cell cycle, apoptosis and anchorage-independent growth. From our point of view, these findings should end up in two clinical implications. First, FTIs should be considered as modulators of genotoxic agents such as standard chemotherapies or radiotherapy. Second, only a partial and incomplete response should be expected from FTIs that could be increased with other relevant targeted agents. Pre-clinical studies confirm that FTIs can be useful in combination therapy and some clinical trials are ongoing.

Phase I studies conclude to a modest activity and a low toxicity for FTIs. Phase II studies favor the use of FTIs in some particular tumors such as glioma, leukemia and breast cancer. Phase III studies are negative but are both conducted in advanced or refractory tumors. We would like to point out that these studies should be interpreted with caution. Until now, FTIs are evaluated like conventional chemotherapy in phase I studies by calculating the maximum tolerated dose (MTD). Nevertheless, MTD appear to be an inappropriate endpoint as no arguments support the fact that ‘higher doses’ equal ‘higher clinical activity’ with such agents. Moreover, if target modulation can be achieved at doses that are lower

5. FTIs in combination

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5.1. Combination with conventional chemotherapy or radiotherapy Pre-clinical studies of FTI-sensitive human tumor cell lines show that combination with cisplatine, taxanes or gemcitabine can improve response [48]. More precisely, combination of FTI and taxanes is sustained by the fact that FTIs sensitize tumor cells to paclitaxel-induced mitotic arrest [49]. Moreover, epothilones synergize with FTI to arrest the growth of prostate cancer cells [50]. One explanation can be provided by the fact that FTIs prevent the farnesylation of centromere-binding proteins and thus induce increased sensitivity to the microtubule-stabilizing action of these compounds. Another combination is sustained by pre-clinical arguments: Zhang et al. [51] have shown that the FTI LB-42722 reverses Rasmediated inhibition of Fas expression. Thus, combination with chemotherapy such as 5-fluoro-uracile which is known to induce apoptosis through the Fas/FasL system should be tested. At a clinical level, many studies of FTIs and standard cytotoxic agents are ongoing. Toxicities appear manageable with evidence of clinical activity in heavily pre-treated patients, some of whom had been resistant to the given cytotoxic as a single agent. Combination of SCH66336 with paclitaxel leads to impressive results with partial response in patients whose disease was refractory to taxanes [52]. Unfortunately, no benefit is reported with the combination of gemcitabine and R115777, in pancreatic cancer [53]. In parallel, combination of FTI with radiotherapy is under investigation. Pre-clinical data have demonstrated that FTIs are radiation sensitizers in selected cell lines. Tumors bearing wild-type [54] or mutated H-Ras [55] can be sensitized to g radiation by FTIs. Recently, we have shown that R115777 reverses the resistance of human glioma cell lines to ionizing radiation [56]. Moreover, while hypoxic cells are markedly resistant to radiation, Cohen-Jonathan et al. [57] have shown that treatment with the FTI L-744, 832 improves the oxygenation of tumor xenografts with H-Ras mutation in nude mice suggesting that FTIs might be useful in the radiosensitization of certain tumors. In clinical trials, complete responses in head and neck or lung cancers have been reported with L-778, 123 and radiotherapy without increase in

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radiotherapy-associated toxicities [58]. One explanation obtained from in vitro studies is that FTIs radiosensitization occurs by accumulation of tumor cells in the G2/M phase of cell cycle [58]. More studies with radiotherapy are ongoing, and the results are awaited with interest. 5.2. Combination with other targeted therapy Anti-tumor effects of FTIs are quite heterogeneous. For example, treatment with R115777 produces a prominent anti-angiogenic response in human colon tumors, an anti-proliferative response in pancreatic tumors and an apoptotic response in melanoma [59]. It is likely that FTIs target different downstream effectors according to host –tumor interactions, histological tumor type and stage of the tumor. Moreover, resistance to FTIs has been reported probably by overexpression of anti-apoptotic proteins. Thus, most of the time, FTIs used as single agent appear to be not sufficient to induce a long-term tumor inhibition. Combination with other well-chosen targeted therapy might synergize with FTIs. For example, Edamatsu et al. [60] have shown that PI3K inhibitors such as LY294002 and wortmannin enhance FTI-induced apoptosis in several cell lines. In agreement with this, Du et al. [47] have demonstrated that inhibition of the PI3K-AKT pathway may unmask the proapoptotic effects of FTIs in malignantly transformed, but not normal, cells. Thus, combination of PI3K inhibitors and FTIs may be of high interest. Another combination is believed to increase FTIs-induced apoptosis: Cdk inhibitors such as roscovitine and olomoucine synergize with FTI to release cytochrome c from mitochondria and to induce apoptosis [60]. FTIs should therefore be evaluated with Cdk inhibitors such as flavopiridol which entered recently clinical trials [61]. Otherwise, Hoover et al. [62] suggested that SCH66336 might be effective in patients with STI571 resistance by enhancing apoptosis providing a rationale for combination trials of Gleevecq and SCH66336. Moreover, Johnston et al. [42] reported that, in breast cancer, most of the responses with FTIs occurred in HER-2/neu positive cancers. Combination of FTIs with trastuzumab (inhibitor of HER-2/neu) has logically been tested with interesting results [63].

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Combination of FTIs with anti-angiogenic agents should also be studied as a synergic anti-metastatic strategy after surgery in tumor with a high-expected rate of metastastic spread. Transformation of cells by oncogenic Ras mutants has been shown to increase the expression of some metalloproteinases, such as gelatinase and stromelysin, which are involved in tumor metastasis [64]. Thus FTIs and metalloproteinase inhibitors should be tested together as potent anti-metastatic combination. Lastly, pre-clinical findings support the combination of FTIs and GGTase-I inhibitors (GGTIs). Whereas FTIs inhibit the farnesylation of H-Ras, they do not completely inhibit the prenylation of Ki-Ras, which remains prenylated in FTI-treated cells because of its modification by the GGTase-I. Therefore, cells transformed with Ki-Ras tend to be more resistant to FTIs than H-Ras-transformed cells. Thus combination of FTIs and GGTIs is an interesting approach for tumors harboring Ki-Ras mutations. Some highly selective inhibitors of GGTase have been conceived but no GGTI are currently in clinical trials. In fact, in contrast to the FTIs, GGTIs seem to have substantial effects on cell signaling in normal cells, inducing cell cycle arrest and apoptosis [65]. Recently Lobell et al. [66] have reported a greater apoptotic response with combination of FTIs and GGTIs than either agent alone in vitro but an important in vivo toxicity associated with GGTI treatment.

5.3. Combination with hormonotherapy Endocrine therapies such as tamoxifen exert their effect at least partially through the modulation of signaling pathways. Recent evidence suggests that estrogen receptor may be involved in non-nuclear estrogen-dependent signaling via interaction with the PI3K/AKT survival pathway [67]. Combination with FTI could thus be interesting since response to FTIs is correlated with dysregulation of the PI3K/AKT pathway in cancer cells. Similarly, in human prostate cancer cells, enhanced anti-tumor effects are observed when the FTI is combined with the anti-androgen bicalutamide [68].

6. Conclusion The development of FTIs is an example of translational research put into practice. Pre-clinical studies have allowed clinicians to use FTIs with interesting results for patients. After 5 years of clinical development, the future of FTIs remains nevertheless dubious. Even if some recent trials have moderated initial enthusiasm, we do think that FTIs are anticancer agents with a promising future. Currently, the biochemical background for their anti-tumor effects is under intense re-evaluation. From our point of view, their development in clinical prospects is now submitted to the elucidation of their mechanism of action and in particular of their downstream effectors. Understanding these mechanisms will provide us relevant biological markers that can, in turn, help clinicians in selection of tumors and patients and in evaluation of efficacy. Moreover, the optimal use of FTIs in therapeutic strategy remains to be elucidated but several lines of evidence argue for a most appropriate use in less advanced tumors or as cytostatic agents. We point out the fact that, based on pre-clinical findings, combination of FTIs with chemotherapy, radiotherapy, hormonotherapy or other targeted agent is synergistic and of clinical relevance.

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