Introduction

Myeloid malignancies, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myeloproliferative–myelodysplastic diseases (eg atypical CML, chronic myelomonocytic leukemia, CMML, juvenile myelomonocytic leukemia, JMML) and myelodysplastic syndromes (MDS) present difficult therapeutic challenges as relapses and complications associated with treatment are common. As many patients with myeloid malignancies are of advanced age and thus more susceptible to the adverse side effects of standard cytotoxic therapies, treatment options are limited. These difficulties may be overcome by therapies, which molecularly target signaling pathways that are involved in the pathogenesis of these malignancies.^1,2,3

A common feature in the molecular pathogenesis of myeloid leukemias is the deregulation of RAS signal transduction. Activated, GTP–bound RAS proteins (H-RAS, N-RAS and the alternatively spliced K-RAS4A and K-RAS4B) transduce mitogenic signals from ligand-stimulated tyrosine kinase, cytokine and heterotrimeric G-protein-coupled receptors. RAS signaling is mediated by binding and activating effector molecules such as Rafs, MEKK, PI-3K and Ral-GEF that regulate proliferation, differentiation and malignant transformation (Figure 1).^{4,5,6,7,8,9,10,11,12} Recent studies have demonstrated that aberrant signaling through the RAS-to-MAP kinase pathway (eg aberrant expression of activated MEK-1:ER or delta Raf:ER proteins) abrogates cytokine dependency and induces transformation of hematopoietic cells.^{13,14,15,16,17,18,19,20,21}

Figure 1.

Simplified scheme describing RAS activation and the cellular consequences of RAS signaling through various effector molecules. RAS proteins are activated by tyrosine kinase receptors (upper right) as well as cytokine receptors (upper left). Activated, GTP-bound RAS binds to and activates effector molecules such as Raf kinase, Ral-GEF and phosphatidyl inositol 3-kinase (PI-3K). RAS signaling through Raf leads to sequential activation of MEK and ERK, resulting in cellular proliferation, differentiation and cell cycle progression (through upregulation of cyclin D1). RAS activation of Ral-GEF causes activation of Rho, which in turn induces stress fiber formation and actin polymerization/depolymerization by regulating PI(4)P5-K, ROCK and Dia. Activation of PI-3K by RAS results in formation of phosphoinositides that recruit PDK1/2 and AKT to the plasma membrane (shown here as an inset below the receptor tyrosine kinase). PDK1/2 activate AKT, PKC, p90^RSK and p70^S6K through phosphorylation, resulting in activation of transcription factors such as c-Myc, activation of glycogen synthase, increased cell survival by inactivation of FKHR and BAD, as well as entry into the cell cycle by activating cyclin D1. There are several ways to inhibit RAS-to-MAPK signaling: (I) inhibiting RAS membrane association (eg FTI, GGTI, PPMTI, REPI and statins); (II) interfering with RAS-Raf interactions (eg sulindac); (III) inhibiting Raf kinase activity (eg Bay439006, GW5074 and ZM336372); and (IV) blocking MEK activation of ERK (eg PD098059, PD184352, U0126 and Ro09-2110).

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One way in which RAS proteins are deregulated is through activating mutations at sites critical for RAS regulation (eg codons 12, 13, 15, 16, 18, 31 and 61) (Figure 2). These mutations increase the half-life of activated RAS-GTP through abrogation of normal intrinsic and/or GAP-stimulated GTPase activity of RAS ^{1,5,7,22,23,24,25,26,27} RAS mutations are frequently observed in AML, JMML and MDS (20–40%).^1,22,23,28 N-RAS is mutated in the majority of the cases and the presence of the mutation is not associated with any particular FAB-type, cytogenetic abnormality or clinical feature including prognosis.²⁸

Figure 2.

Illustration of the different domains and motifs contained in RAS proteins. The effector domain confers RAS with the ability to bind RAF, Ral-GDS and PI-3K. Switch regions I and II have different conformations, depending upon whether RAS is bound to GDP or GTP. The four RAS isoforms (H-RAS, K-RAS4A, K-RAS4B and N-RAS) differ in the heterogeneous region. The C-terminal CAAX box motif is important for prenylation, which enables RAS proteins to bind to the cell membrane. Activating RAS mutations that have been found in human tumors are depicted by the black points.

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In addition to activation by mutation, indirect deregulation of RAS through mutations of other oncogenes or tumor suppressor genes has also been implicated in myeloid leukemias.^1,2 The importance of RAS is underscored by the positioning of several oncogene and tumor suppressor gene products on this pathway.^1,2,3,4,5 This includes constitutive activation of proto-oncogenes such as receptor (colony-stimulating factor-1 (CSF-1) receptor, c-Kit receptor, FLT3 receptor, TEL-PDGFR) and/or nonreceptor tyrosine kinases (BCR-Abl, Abl-TEL) or inactivation of tumor suppressor genes (NF-1) (Table 1).^{1,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46}

Table 1 - RAS activation in hematological malignancies (modified from Reuter et al¹).

Full table

Single point mutations can result in constitutive activation of normal receptor tyrosine kinases (eg CSF-1 receptor, c-Kit receptor, FLT3 receptor). Additionally, activating tandem internal duplication of the FLT3 receptor has been reported in at least 20% of adult AML,^{35,47,48,49,50,51} but is less common in childhood AML.^52,53,54 Interestingly, tyrosine kinase inhibitors herbimycin A and AG1296 have been demonstrated to inhibit growth and downstream signaling of leukemia cells transformed with mutant FLT3.^55,56 Furthermore, Hsp90 inhibitors were reported to selectively induce apoptosis of tandemly duplicated FLT3-transformed leukemia cells.⁵⁷ Members of the c-Kit/c-FMS receptor kinase family (eg c-Kit, c-FMS, FLT3) are linked with components of the RAS-to-MAPK signaling pathway (eg Grb-2, Shc and ERK), suggesting that activating mutations of c-FMS and FLT3 may induce activation of RAS.^35,56,57,58

Many different types of chimeric proteins resulting from translocations involving receptor tyrosine kinases have been found in human hematological malignancies (Table 1).^29,59 Several Tel fusion proteins have been reported, including Tel-PDGFR, Tel-Abl, Tel-ARG Tel-Jak2 and Tel-TRKC. Abl is a nonreceptor tyrosine kinase that is also mutated and activated in CML.^40,60,61 In Bcr-Abl, the product of the t(9;22) translocation, the N-terminal Bcr portion serves as an oligomerization domain. Bcr-Abl is a constitutively activated cytosolic tyrosine kinase that causes abrogation of growth factor dependence, blockade of differentiation and direct inhibition of apoptosis. Although RAS mutations are extremely rare in CML, increased levels of GTP-RAS have been demonstrated in Bcr-Abl-positive cells.^40,60,61 Thus, deregulation of RAS function appears to be a common theme in transformation by activated receptor and nonreceptor tyrosine kinases. RAS activation may cause elevated cell cycle progression and inhibition of apoptosis.^{28,29,40,59,60,61}

In addition to oncogenes, tumor suppressor genes have been implicated in RAS deregulation. Neurofibromin (NF-1), a RAS-GTPase activating protein (GAP), is mutated in autosomal dominant-type 1 neurofibromatosis, which is associated with an increased tendency to develop myeloid leukemias, especially JMML.^42,43,44,45 JMML (15–30%) cases lacking NF1 mutations have activating RAS mutations⁶² and leukemic cells from children with neurofibromatosis type 1 have moderately elevated levels of GTP-RAS.^42,43,44,45 The observation that human JMML cells exhibit hypersensitivity to granulocyte/macrophage CSF-1 suggests a common pathophysiological mechanism involving downstream RAS signaling.^45,62,63 Uncontrolled stimulation of mitogenic signal transduction pathways is at least partially responsible for the resulting transformation.^1,22,23 These observations make RAS and the RAS-to-MAP kinase pathway an interesting target for the development of new anticancer agents.

RAS signaling can be inhibited by blocking its membrane localization, by inhibiting RAS protein expression (eg antisense, ribozyme), by disrupting RAS–RAF interactions (eg sulindac) and by inhibiting downstream targets (eg RAF kinase and MAPK kinase inhibitors).^1,64,65 Inhibitors of RAS signaling revert RAS-dependent transformation and cause regression of RAS-dependent tumors in animal models.¹ Since farnesyltransferase inhibitors (FTIs) are the most advanced of these novel therapeutics and are currently tested in clinical trials, this review will focus on the biological effects, efficiency and limitations of these inhibitors.

RAS post-translational modification

RAS activation and signaling depend on post-translational modification of cytoplasmatic precursors thus translocating RAS to the cell membrane. These modifications include farnesylation, proteolysis, methylation and palmitoylation (Figure 3).^1,2,66,67 Farnesyltransferase (FTase) catalyzes the first irreversible step of RAS modification. FTase transfers a farnesyl group from farnesyl diphosphate (FPP) to the cysteine residue of the CAAX motif. FTase is a Zn²⁺-dependent heterodimeric enzyme.^66,67 Both the and subunits of mammalian RAS FTase are composed mostly of helices.⁶⁸ In the presence of FTIs, K- and N-RAS proteins can be alternatively prenylated by geranylgeranyl transferase I (GGTase I), which transfers a geranylgeranyl moiety from geranylgeranyl pyrophosphate (GGPP) to the C-terminal cysteine of the CAAX motif (Figure 3). While the preferred recognition motif for FTase and GGTase I is a carboxyl-terminal CAAX (where C is cysteine, A is an aliphatic amino acid and X is any amino acid), GGTase II prenylates proteins with C-terminal CXC, XXCC or CCXX sequences. Although FTase and GGTase I demonstrate selective substrate specificity for prenyl donors and acceptors under normal cellular conditions, these two enzymes have some degree of cross specificity.^66,67 While GGPP binds competitively with FPP to FTase, only FPP serves as an effective substrate. In contrast, FPP serves as a moderately effective substrate for GGTase I but binds less efficiently (more than 300-fold lower) to GGTase I as compared to GGPP.⁶⁹

Figure 3.

Overview of RAS post-translational modification and differences in membrane association among the four RAS isoforms. RAS proteins are produced as cytoplasmatic precursors that require several modifications to stably bind to the plasma membrane. Under normal cellular conditions, FTase covalently attaches a farnesyl group to the thiol of the C-terminal cysteine residue in the CAAX box motif of the RAS proteins. Rce1 then catalyzes the proteolysis of the terminal tripeptide, and the truncated protein is further modified by carboxymethylation of the farnesylated, C-terminal cysteine via Icmt. While H-RAS, K-RAS4A and N-RAS are then palmitoylated to further aid membrane association, K-RAS4B contains a lysine-rich region (KKKKKK), which directs this isoform to the cell membrane. Note that in the presence of FTI, K- and N-RAS can be alternatively prenylated by geranylgeranyl transferase I. In contrast, H-RAS is not a substrate for GGTase I and so remains an inactive, cytosolic precursor protein in the presence of FTI. Abbreviations : FPP, farnesyl pyrophosphate; FTase, farnesyltransferase; Me, methyl; F, farnesyl; P, palmitoyl; FTI, farnesyltransferase inhibitor; GGPP, geranylgeranyl pyrophosphate; GGTase I, geranylgeranyl transferase I; GGTI, geranylgeranyl transferase I inhibitor.

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In a second step, Rce1 catalyzes proteolysis of AAX from the farnesylated CAAX motif of RAS. Carboxymethylation of the farnesylated C-terminal cysteine of RAS is then carried out by Icmt. As Rce1 and Icmt are found in the endoplasmatic reticulum (ER), RAS proteolysis and carboxymethylation occur on the cytosolic membrane of the ER (Figure 3).⁷⁰

In addition to the CAAX motif, a lysine-rich sequence in the hypervariable region in K-RAS4B (residues 175–180) or palmitoylation of cysteine 180 in K-RAS4A, cysteine 181 in N-RAS or cysteines 181 and 184 in H-RAS also direct membrane localization. While H- and N-RAS traffic via the classical secretory pathway through the golgi to caveolae and lipid rafts, poly-basic K-RAS4B is largely excluded from the golgi and is transported to the plasma membrane via golgi-independent pathways. Interestingly, the differential plasma membrane microlocalization of RAS isoforms is an important determinant of which effector molecules the RAS proteins associate.⁷⁰

Farnesyltransferase inhibitors: preclinical studies

The dramatic effects of FTIs on various types of cancer cells have been extensively studied and reviewed.^{1,65,71,72,73,74,75} Some of these effects include: (1) inhibition of anchorage-dependent growth; (2) changes in cell cycle progression (eg accumulation of cells in G₀/G₁ or G₂/M phases of the cell cycle, depending on cell type); (3) induction of apoptosis; and (4) effects on actin stress fibers and cell morphology. Although FTIs were originally designed as RAS-FTIs, multiple farnesylated proteins found in mammalian cells have been characterized as potential targets of FTI action (Table 2). These potential FTI targets include (1) small G-proteins (eg RAS, Rap2, Rho proteins), (2) centromere binding proteins (eg CENP-E, CENP-F), (3) tyrosine phosphatases, (4) proteins involved in visual signal transduction (eg cGMP-PDE , cGMP-PDE ), (5) proteins involved in nuclear membrane structure (eg Rho proteins, TC10), and (6) inositol signaling proteins and others.

Table 2 - Substrates of Farnesyltransferase (modified from Tamanoi et al⁷⁵).

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Some of the farnesylated proteins in mammalian cells that are involved in the multiple cellular effects induced by FTIs in cancer cells have been identified. FTI-induced G₁ arrest may be due to induction of p21^WAF1/CIP1. In contrast, FTI-induced G₂/M arrest is a consequence of altered microtubule–centromere interaction during mitosis by blocking bipolar spindle formation and chromosome alignment.⁷⁶ It has been suggested that FTI-induced accumulation of cells in prometaphase is due to inhibition of farnesylation of the centromeric protein CENP-E.⁷⁷ However, as CENP-E is not essential for spindle pole separation, others have suggested that dynein- or Eg5-interacting proteins may be more relevant biologic FTI targets, and are responsible for the prometaphase arrest.⁷⁶

FTIs have been demonstrated to induce apoptosis in a wide variety of cancer cell lines by release of cytochrome c from mitochondria into the cytosol.⁷⁵ Cytochrome c forms a complex with Apaf-1 and procaspase-9 that results in activation of caspase-9 and -3. Caspase-3 is a key regulator that triggers a variety of apoptotic changes, including nuclear condensation and chromosomal DNA fragmentation.⁷⁵ Additionally, inhibition of phosphoinositide 3-OH kinase/AKT2-mediated cell survival and adhesion pathway was recently shown as a critical target for FTI-induced apoptosis.⁷⁸ Interestingly, it has recently been demonstrated that the common alpha subunit of FTase and GGTase I is cleaved by caspase-3 during apoptosis, suggesting that inactivation of prenyltransferases by caspases contributes to progression of apoptosis.⁷⁹

The molecular mechanisms by which FTIs induce morphological changes, induction of microtubule assembly and phenotypic reversion are not fully understood. However, it has been demonstrated that FTIs inhibit farnesylation of nuclear lamins, which are intermediate filaments critical for providing cells with mechanical strength. Multiple lines of evidence suggest that the dynamic organization of the actin cytoskeleton is regulated by Rho family GTPases (eg Rac1, RhoA, Cdc42).^{80,81,82,83,84} At least three effectors of Rho that are linked to actin reorganization have been identified (eg Dia, ROCK, PI(4)P5-K) (Figure 1). Activation of ROCK by Rho induces phosphorylation of myosin light chain and, together with Dia, leads to stress fiber formation. While ROCK seems to be involved in actin depolymerization, Dia and PI(4)P5-K induce actin polymerization. RhoB has been shown to be both farnesylated and geranylgeranylated, and has been proposed as a key target of FTIs.⁸⁵ These studies examined epitope-tagged RhoB that is expressed after transfection. It has been suggested that FTI treatment shifts the prenylation status of RhoB to an exclusively geranylgeranylated form that induces apoptotic and antineoplastic responses, including phenotypic reversion and loss of anchorage independence.^85,86,87,88 However, induction of apoptosis by overexpression of either farnesylated (RhoB-F) or geranylgeranylated (RhoB-GG) versions of RhoB in Panc-1 cells suggests that both RhoB-F and RhoB-GG function similarly and argues against the idea that RhoB-GG has a role different from that of RhoB-F.⁸⁹ In addition to RhoB, other members of the Rho family are also farnesylated and important for stress fiber organization and cellular morphology (eg RhoD, RhoE, Rho6 and Rho7).⁷⁵

Other classes of prenylation inhibitors: GGTIs and inhibitors of isoprenoid biosynthesis

Inhibitors of geranylgeranyl transferase I

Many efforts at inhibiting the function of RAS have focused on FTase, which prenylates all four RAS isozymes (H-, K4A-, K4B- and N-RAS) under normal conditions. However, K- and N-RAS are alternatively prenylated by GGTase I in the presence of FTIs.^90,91 This cross prenylation of K- and N-RAS results in fully functional and, in the case of mutant RAS, transforming proteins. As K- and N-RAS are mutated in most human cancers including AML, blocking K- and N-RAS signaling by inhibition of FTase and GGTase I is an attractive strategy to combat these diseases.^{92,93,94,95,96} Since the development of the first GGTase I inhibitors (GGTIs) by Sebti and Hamilton, potent inhibitors of GGTase I and both prenyltransferases (dual prenylation inhibitors=DPIs) have been developed. The dual inhibitor L-778,123 has entered clinical trials.^94,95,97 All reported GGTIs were designed based on the CAAX motif or GGPP and are characterized by varying selectivity towards GGTase I and FTase. GGTIs-286/287 and GGTIs-297/298 have only a three- to seven-fold selectivity for GGTase I relative to FTase.^98,99,100 In contrast, GGTIs-2133/2147 are more specific for GGTase I as compared to FTase (eg 60- to 140-fold).¹⁰¹ While GGTI-286 and GGTI-298 are equipotent in whole cells, substitution of the phenyl group in GGTI-286 by a naphthyl group as in GGTI-298 has been reported to increase the selectivity towards GGTase I over FTase in whole cells.¹⁰⁰ The dual inhibitor L-778,123 has a 50-fold preference for FTase over GGTase I.^97,102 GGTIs have been demonstrated to inhibit the growth of tumor cell lines and human tumor xenografts in mice.^103,104 GGTI treatment of tumor cell lines has been shown to cause cell cycle arrests in G₀/G₁ via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1).^105,106,107 Several potent GGTIs, FTIs and DPIs were recently evaluated in combinations in preclinical models.⁹⁴ Although FTI/GGTI combinations elicited greater apoptotic responses than either agent alone, treatment with these particular GGTIs (eg GGTI-1 and GGTI-2) in vivo was poorly tolerated. This observation is in contrast to earlier studies by Sun et al, who did not report any nonspecific toxicites associated with GGTI treatment (GGTI-297 and GGTI-2154).^103,104 It was speculated that the toxicities caused by GGTI-1/-2 are unrelated to the inhibitory effect on GGTase I and inherent to the GGTI class of compounds used in the study by Lobell et al.⁹⁴ While these results suggest that some classes of GGTIs may elicit unspecific toxicity, other GGTIs might be useful as antineoplastic agents in a clinical setting either alone or in combination with other agents (eg FTIs, statins).

Inhibitors of HMG-CoA reductase

Inhibition of hydroxy- methylglutaryl coenzyme A reductase (HMG-CoA reductase) impairs post-translational processing of RAS and RAS-related proteins by depletion of mevalonate (Figure 4). Statins inhibit the conversion of HMG-CoA to mevalonate by competitively inhibiting HMG-CoA reductase. As this topic has recently been a focus of several reviews,^108,109 this paper will focus on the implication of the mevalonate pathway for protein prenylation. Statin treatment of susceptible cells has been shown to cause cell cycle arrests in the G₁/S phase.^110,111 This effect was demonstrated to be mediated through upregulation of the CDK inhibitors p21(WAF1/CIP1) and/or p27^Kip1 and downregulation of cyclin-dependent kinase (CDK) 2.^{112,113,114,115}

Figure 4.

Flow chart depicting isoprenoid biosynthesis. As shown in this diagram, statins interrupt isoprenoid biosynthesis by inhibiting HMG-CoA reductase. Statin treatment results in loss of isoprenoid species (eg farnesyl pyrophosphate, geranylgeranylpyrophosphate) necessary for post-translational modification of many proteins, thus blocking protein modification, and causing cytoplasmatic accumulation of proteins such as RAS, Rho, and Rheb. Farnesyltransferase inhibitors (FTI) and geranylgeranyl transferase inhibitors (GGTI) can also block protein post-translational modification through inhibition of the respective enzymes (ie FTase or GGTase).

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Recently, it was reported that lovastatin induces differentiation in AML including increased expression of CD11b and CD18 similar to retinoic acid treatment.¹¹⁶ Additionally, downregulation of the antiapoptotic gene bcl-2 was observed, which is associated with late stage differentiation of the myeloid lineage.

Furthermore, statin treatment induces apoptosis in sensitive tumor cells.^109,117 Lovastatin induced apoptosis in the majority of AML cell lines and primary AML cells investigated.^{118,119,120,121} In AML, statin-induced apoptosis is a result of cyctochrome c release, activation of caspase-3 and PARP cleavage.¹²² It has been demonstrated that mevalonate depletion is responsible for statin-induced apoptosis. Add-back experiments have recently shown that only GGPP (and not FPP or squalene) was able to inhibit apoptosis, suggesting that protein geranylgeranylation is a pivotal element for the cytotoxic effects of statins.^123,124 However, the identity of the geranylgeranylated substrate(s) and their downstream pathways, which are essential for the statin effects, are still unknown.¹⁰⁹ Statin treatment enhances the antiproliferative activity of several standard therapeutic agents in AML cells including cytarabine and others.^125,126 Statins have shown antiproliferative activity in several preclinical tumor models including AML.¹⁰⁹ Simvastatin had an inhibitory effect on the proliferation of human AML cells in SCID mice.¹²⁷ As this effect was independent of the presence of RAS mutations, it was suggested that the inhibitory statin effect was independent of the RAS signaling pathway. However, activation or upregulation of RAS signaling was not investigated. Statins as anticancer agents have also been investigated in several human malignancies including AML.^109,128 The achievable plasma concentrations at a lovastatin dose of 25 mg/kg/day were 0.1 to 3.92 M, which corresponds to the concentrations required to trigger apoptosis in vitro.¹⁰⁹ Recently, a phase I/II trial to evaluate the safety and efficacy of lovastatin in refractory AML patients was reported. Lovastatin was administered at 10–20 mg/kg/day for 2 weeks followed by 2 weeks off. This regimen was limited by drug-related toxicities including nausea and elevated levels of creatinine phosphokinase. A lower dosage of lovastatin (eg 2 mg/kg/day) for 54 days caused blast cell reduction in an elderly female patient with relapsed AML. The patient's AML cells were also reported to be sensitive to lovastatin-induced apoptosis in vitro.^109,128

Although statin toxicity has been attributed to the inhibition of RAS or Rho prenylation, a recent study suggests that cellular cholesterol might be critical to cell survival.¹²⁹

Farnesyltransferase inhibitors: clinical studies in myeloid leukemias

While hundreds of FTIs have been developed and designed or isolated from natural products, so far only four have entered clinical trials (Figure 5). Several distinct classes of compounds have been developed, including FPP analogues which mimic the farnesyl motif, CAAX analogues which mimic the CAAX motif (=peptidomimetics) and bisubstrate inhibitors which mimic both the FPP and the CAAX motif.^{1,2,71,72,73,74,75}

Figure 5.

Shown here are the chemical structures of four farnesyltransferase inhibitors that have been tested in human clinical trials.

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R115777

The methylquinolone R115777 (=Tipifarnib, Zarnestra^TM), initially developed as an antifungal agent, is a selective nonpeptidomimetic FTI with oral bioavailability. R115777 inhibits farnesylation of lamin B and K-RAS in vitro with IC₅₀s of 0.86 and 7.9 nM, respectively.¹³⁰ In preclinical studies, R115777 inhibited the growth of tumor cell lines and xenografts with or without RAS mutations.^131,132 Cells harboring H- or N-RAS mutations were found to be more sensitive than those containing K-RAS mutations. R115777 has already been tested in several phase I trials in patients with advanced cancer.^{133,134,135,136} Dose-limiting toxicities (DLTs) were grade 3 neuropathy, and grade 3–4 myelosuppression. The observation of myelosuppression in patients treated with FTI is consistent with a preclinical study in which proliferation of CD34+ cells was demonstrated to be inhibited by FTI treatment.¹³⁷ The most frequent clinical grade 2 or 3 adverse events included nausea, vomiting, headache, fatigue, anemia and hypotension. Additionally, renal insufficiency, polydipsia and paresthesias were observed.¹³⁴ The recommended dose for phase II/III testing was 300–600 mg twice daily (b.i.d). R115777 has also been combined with other agents (eg 5-fluorouracil/leucovorin, topotecan, docetaxel, capecitabine, irinotecan, trastuzamab, gemcitabine) in phase I studies. Some of the combination studies in patients with solid tumors have demonstrated antitumor activity, including partial and complete remissions.¹³⁰ However, in a combination with gemcitabine, R115777 did not prolong overall survival in patients with advanced pancreatic cancer as compared to gemcitabine monotherapy (Van Cutsem et al. Proc Am Soc Clin Oncol 2002, www.asco.org, abstract 517).

A dose-escalation trial of R115777 was also performed in 35 adults with refractory and relapsed acute leukemias (including 25 AML, three CML-BC, six acute lymphoblastic leukemia (ALL), one not evaluable). RAS mutations were not found in any of the 35 leukemia patients. Maximally tolerated dose (MTD), toxicities and pharmacokinetics were determined in this study. R115777 doses ranged from 100 mg b.i.d. to 1200 mg b.i.d. for up to 21 days. DLTs occurred at 1200 mg b.i.d., with central neurotoxicity such as ataxia, confusion, and dysarthria. Plasma pharmacokinetics demonstrated a linear relation between dose and C_max or AUC_12 h for all dose levels tested. R115777 was shown to accumulate in the bone marrow in a dose-dependent fashion. Clinical responses occurred in 10 of 34 patients (29%), including 2 complete remissions.¹³⁴ R115777 is currently tested in several phase II studies in hematological malignancies such as myeloproliferative disorders (Ph+ and Ph- CML, CMML), childhood leukemia, high-risk MDS, and postconsolidation therapy in AML (Table 3). Interim results from a multicenter, open-label phase II trial in patients with relapsed and refractory AML demonstrated reductions in bone marrow leukemic blasts (to <5%) in seven of 42 evaluable patients. The most frequent grade 3–4 drug-related adverse events were hypokalemia, rash and hyperbilirubinemia (Harousseau et al. Proc Am Soc Clin Oncol 2002; 21: 265a; abstract 1056). Preliminary results of a recent phase II trial of R115777 in previously untreated patients with poor-risk AML and MDS using 600 mg b.i.d. for 21 days on a cyclic basis showed complete or partial responses in 10 of 30 (33%) evaluable patients (eight CR, two PR). In nine of these patients, responses occurred following one cycle of therapy. Grade 4 nonhematologic toxicities were observed in 6 of 36 patients (mostly infections associated with neutropenia), while grade 3 or 4 neutropenia and thrombocytopenia were observed in most patients (Lancet et al. Blood 2002; volume 100: 560a; abstract 2200). R115777 also showed clinical activity in CML, poor-risk MDS and CMML irrespective of the presence of RAS mutations, while all multiple myeloma cases were found to be resistant (Table 3). In another phase I/II study, R115777 (600 mg b.i.d.) resulted in transient partial or complete hematologic responses in seven of 22 patients with CML. The median duration of the responses was 9 weeks (range 3–23 weeks). Four patients had a minor genetic response. Two of eight patients with myelofibrosis had a significant decrease in splenomegaly, one had normalization of white blood cell counts and differential, and one became transfusion independent. A slight reduction (34%) in monoclonal protein was achieved in one patient with multiple myeloma. Adverse events and toxicities included grade 2 nausea (55%), grade 3–4 fatigue (48%), grade 3–4 skin rash (10%), grade 3–4 peripheral neuropathy (5%), and liver toxicity (5%).¹³⁸

Table 3 - Phase I and II trials of FTIs in myeloid malignancies.

Full table

SCH66336

The FTI SCH66336 (=Lonafarnib, Sarasar^TM) is an orally bioavailable, nonpeptide tricyclic inhibitor of the CAAX binding site of FTase. Several preclinical studies with this compound have demonstrated growth inhibition of human tumor cell lines and potent antineoplastic activity in nude mice bearing human bladder, lung, colon, pancreas and prostate cancer xenografts.^{139,140,141,142} The IC₅₀ values for H-RAS and K-RAS prenylation inhibition were determined to be 1.9 and 5.2 nM, respectively. Interestingly, SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in a NCI-H460 lung cancer xenograft model and in transgenic mice of the wap-ras/F substrain that spontaneously develop mammary tumors.¹⁴³ Synergy of SCH66336 and cisplatin was also reported in several human cancer cell lines.¹⁴⁴ SCH66336 was reported to have activity against Bcr-Abl-induced murine leukemias and primary human CML cells.¹⁴⁵ Furthermore, treatment of Bcr-Abl+ ALL in P190 transgenic mice with SCH66336 resulted in an 80% survival rate in contrast to the control group.¹⁴⁶ Additionally, SCH66336 was shown to inhibit STI571-resistant Bcr-Abl+ cell lines and hematopoietic colony formation of peripheral blood samples from STI571-resistant CML patients. Moreover, SCH66336 enhanced STI571-induced apoptosis.^147,148

A phase I study of cyclic oral administration of SCH66336 given twice a day for 7 days out of a 21-day cycle in patients with advanced solid tumors was performed to evaluate the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FTase in vivo. Dose-limiting factors were diarrhea, nausea, vomiting and fatigue at 400 mg b.i.d. Mild, reversible renal insufficiency secondary to volume depletion and grade 2 hematological toxicity was also observed. SCH66336 was shown to inhibit prelamin A farnesylation in buccal mucosa cells of patients and one partial response was observed in a patient with previously treated metastatic nonsmall cell lung cancer.¹⁴⁹ The recommended phase II dose for SCH66336 was determined to be 350 mg b.i.d. for this schedule. Phase I studies for SCH66336 in patients with solid tumors using a 2-week on, 2-week off schedule and a continuous oral schedule were also reported (Hurwitz et al. Proc Am Soc Clin Oncol 1999, www.asco.org, abstract not available).¹⁵⁰ In both studies, the recommended phase II dose was 200 mg b.i.d. While toxicities were similar in the cyclic administration schedules, continuous treatment led to DLTs including grade 4 neutropenia and thrombocytopenia, grade 4 vomiting and grade 3 neurocortical toxicity. Other toxicities included diarrhea, mild anorexia, weight loss, fatigue and bradycardia. No major responses were reported in these trials. Phase I and II trials of continuous oral administration of SCH66336 in patients with advanced hematological maligancies were recently reported (Table 3) (Cortes et al. Blood 2002, 100; 793a; abstract 3132; List et al. Blood 2002; 100: 789a; abstract 3120). In the phase I trial, SCH66336 was administered continuously beginning at 200 mg b.i.d., with escalations of 100 mg/dose in subsequent cohorts. DLTs were observed at 300 mg b.i.d., including grade 3 diarrhea, which was unresponsive to medication and grade 4 hypokalemia. Diarrhea, nausea and vomiting were the most common treatment-related toxicities. Farnesylation of the chaperone protein DNAJ was inhibited at both dose levels. Clinical activity was observed in six of 16 patients, including hematological improvement (according to the International working group, IWG) in three of five CMML, decrease in white blood cell count and blast count in 2 of 3 CML-bc and 1 Ph+ ALL patient. The dose recommended for phase II studies was 200 mg b.i.d. Currently, SCH66336 is tested in an open label phase II study in 54 patients with advanced hematological malignancies (eg CML-bc, CMML, RAEB, RAEB-t, relapsed or refractory AML or ALL). Responses have been reported in 10 of 54 patients (19%). Responses include reduction in blast count in one of 19 AML, hematological improvement in three of 15 MDS, and normalization of monocyte counts in six of 12 CMML patients (Cortes et al. Blood 2002; 100: 793a; abstract 3132). Additionally, another phase I–II study of SCH66336 was reported in patients with MDS or secondary AML. SCH66336 was administered at 200 mg b.i.d. for three courses of 4 weeks separated by 1–4 weeks off treatment. Gastrointestinal toxicity (nausea, diarrhea, vomiting) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection and another developed atrial fibrillation leading to termination of treatment. Dose reductions were performed in most patients with more than one course. Two partial responses were observed (IWG criteria) in one patient with RAEB and in another with sAML M6 (Ravoet et al. Blood 2002; 100: 794; abstract 3136).

BMS-214662

FTI BMS-214662 is an imidazole-containing tetrahydrobenzodiazepine, which has a 1000-fold selectivity for FTase over GGTase.¹⁵¹ BMS-214662 inhibited the farnesylation of H-RAS with a K_i of 0.93 nM, while it is five-fold less potent with K-RAS as a substrate. In preclinical studies, BMS-214662 demonstrated activity against several human tumor xenografts, including HCT-116 and HAT-29 colon, MiaPaCa pancreatic, Calu-1 lung and EJ-1 bladder carcinomas.¹⁵² Several phase I studies have investigated the efficacy of BMS-214662 as a single agent in patients with solid tumors. The drug was administered orally or by intermittent infusion. In phase I studies using oral BMS-214662 at doses of 50–150 mg/day for 14 days every 21 days, systemic exposure was often limited by adverse gastrointestinal effects (eg nausea, vomiting, diarrhea, anorexia). DLT were grade 3 nausea and diarrhea at 150 mg/day. In another phase I study (68–168 mg/m² given every 3 weeks) in patients with advanced solid tumors, mean bioavailability ranged between 25 and 36% resulting in reduced inhibition of FTase activity in peripheral blood mononuclear cells (Sonnichsen et al. Proc Am Soc Clin Oncol 2000, www.asco.org, abstract 691). Due to gastrointestinal toxicities, the oral form of BMS-214662 has been abandoned. Intravenous administration of BMS-214662 was also studied in several phase I trials in patients with solid tumors. Several dosing schedules were used, including (1) 1 or 4 hour infusion every 3 weeks (28–102 mg/m² and 75–225 mg/m²), (2) once weekly for 4 weeks followed by 2 weeks of rest (36–225 mg/m²) and (3) 24 h infusion weekly (56–300 mg/m²) (Ryan et al. Proc Am Soc Clin Oncol 2000, www.asco.org, abstract 720; Kim et al. Proc Am Soc Clin Oncol 2001, www.asco.org, abstract 313; Mackay et al. Proc Am Soc Clin Oncol 2001, www.asco.org, abstract 315; Tabernero et al. Proc Am Soc Clin Oncol 2001, www.asco.org, abstract 304 ; Voi et al. Proc Am Soc Clin Oncol 2001, www.asco.org, abstract 312; Zhu et al. Proc Am Soc Clin Oncol 2002, www.asco.org, abstract 366). Observed toxicities included elevation of transaminases, nausea, vomiting, diarrhea, fatigue, somnolence and anorexia. Leucopenia and neutropenia were also observed. No grade 3 and 4 toxicities have been reported. Some evidence of activity was reported, including tumor regression in patients with lung (NSCLC), colorectal, prostate, laryngeal and breast cancer. A weekly dose of 245 mg/m² was recommended for a phase II study. BMS-214662 has also been tested in a phase I trial in patients with refractory or relapsed acute leukemias (13 AML, six MDS, three ALL) (Table 3). Median age was 53 years (range 22–74 years). BMS-214662 was given as a 1-h intravenous infusion weekly without interruption until toxicity or disease progression (42–157 mg/m²). Two patients receiving 157 mg/m² had grade 3 toxicity (eg supraventricular tachycardia with QTc prolongation and diarrhea). No grade >3 toxicity was observed. Five patients (three AML and two MDS) had a >50% reduction in bone marrow blasts (in four patients <5%). One patient with RAEB had an improvement of platelets and neutrophils (Cortes et al. Blood 2001; 98: 594a; abstract 2489).

L-778,123

L-778,123 is a peptidomimetic FTI administered as an i.v. infusion. L-778,123 is a potent inhibitor of FTase (in vitro IC₅₀ 2 nM) that also has activity against GGTase I (in vitro IC₅₀=98 nM). This dual inhibitor was developed in part because it completely inhibited K-RAS prenylation in cell lines.¹⁰² However, in initial tests in humans, L-778,123 failed to inhibit K-RAS prenylation.⁹⁵ A dose-escalation trial of L-778,123 was performed in 25 patients with advanced solid malignancies (colorectal, pancreatic, renal cell, bladder and other cancers).¹⁵³ L-778,123 was administered as a continous i.v. infusion for 7 days every 3 weeks at doses ranging from 35 to 1120 mg/m²/day to determine toxicities, MTD dose and pharmacokinetics. At 1120 mg/m²/day, DLTs consisted of grade 4 thrombocytopenia, significant prolongation of the QT_c interval (in one of 25 patients) and profound fatigue. More protracted continuous i.v. administration schedules (eg 2–4 weeks) of L-778,123 resulted in similar DLTs at 840 mg/m²/day. Similar DLTs were also observed in preclinical toxicity studies. At 560 mg/m²/day, myelosuppression was mild to moderate and QT_c prolongation was negligible. Therefore, this dose was recommended for subsequent phase II studies irrespective of whether the agent is administered as a protracted infusion continuously for 1, 2 or 4 weeks. Pharmacokinetics were linear and steady-state L-778,123 plasma concentrations exceeded IC₅₀ values required for growth inhibition and cytotoxicity in preclinical studies (mean 8.093.11 M at 560 mg/m²/day vs range between 0.07 and 5.35 M). L-778,123 was also tested in a phase I trial in combination with radiotherapy for locally advanced lung and head and neck cancer. No DLTs were observed at 280 mg/m²/day during weeks 1, 2, 4 and 5 of radiotherapy, while grade 4 neutrophilia occurred at 560 mg/m²/day during weeks 1, 2, 4, 5 and 7. Local responses have been observed in four NSCLC patients.¹⁵⁴ This compound has so far not been tested in hematological malignancies.

Mechanisms of FTI resistance

While FTIs have shown promise in some phase I/II trials, resistance to FTI treatment has also been reported. In a recent phase III clinical trial of FTI R115777 in patients with pancreatic cancer, no beneficial effects from FTI treatment were observed. As pancreatic cancers predominantly harbor K-RAS mutations, these results suggest that FTIs might be inefficient in malignancies harboring K-RAS mutations. In agreement with these clinical results, earlier reports described resistance to FTI treatment in K- or N-RAS transformed cells^99,155,156 as well as in mouse models containing mutated K- and N-RAS-induced tumors.^157,158,159

As RAS mutations in human malignancies, including myeloid leukemias, predominantly occur in K- and N-RAS, it is critical to understand how these RAS isoforms limit the efficiency of FTIs.^1,22,23 Resistance of K-RAS processing to inhibition by FTIs may be due to the high binding affinity of K-RAS to FTase.^156,160

Another potentially major factor which may contribute to FTI resistance could be the existence of a cellular response which allows alternative prenylation of the biologically relevant locus (loci?) of FTIs. It has been demonstrated that although all RAS proteins are normally farnesylated in vivo, K- and N-RAS become geranylgeranylated by GGTase I in the presence of FTIs.^90,91,99 This alternative geranylgeranylation of K- and N-RAS enable these RAS isoforms to associate with the plasma membrane, thus retaining full biologic activity, including transforming ability.^160,161 In addition to K- and N-RAS, alternative cross-prenylation of other proteins by GGTase I (eg RhoB) may be involved in the natural resistance of tumor cells to FTI treatment.

One strategy to overcome the alternative geranylgeranylation of K- and N-RAS is cotreatment of the tumor cells with FTI and GGTI. Several reports have demonstrated synergistic cytotoxicity of FTI/GGTI cotreatment in adrenocortical, human colon cancer and myeloid leukemia cells containing mutant K-RAS.^92,93,96 The FTI/GGTI cotreatment strategy has recently been employed in K-RAS transgenic mice with mammary tumors.⁹⁴ In agreement with previous studies, this treatment resulted in a dose dependent decrease of K-RAS prenylation and tumor regression.^103,104 However, in contrast to previous reports using CAAL-based GGTIs in mouse xenograft models, the GGTIs described by Lobell et al⁹⁴ elicited high toxicity in the mouse models.

Recently, a variant ras-transformed cell line was identified, which was resistant to phenotypic reversion by FTI.¹⁶² This phenomenon was not due to mutation of the FTase subunits, changes in intracellular drug accumulation, or amplification of the multiple drug-resistance (MDR) gene. The precise mechanism of resistance in these cells remained unclear. However, mutation of FTase might also lead to resistance towards FTI, as it has been reported that the Y361L mutant of FTase exhibits increased resistance to FTI and is able to farnesylate substrates possessing CIIS carboxy termini.¹⁶³

Withdrawal of FTI from successfully treated tumor-bearing mice lead to subsequent tumor growth in the absence of the drug. A second FTI treatment resulted in a second response in some mice, but some tumors were found to become resistant to FTI.¹⁵⁷ Therefore, uninterrupted treatment with FTI might be required. Recently, an FTI-resistant human colon cancer cell line was established and characterized.¹⁶⁴ While FTI-resistance did not appear to be related to differences in drug efflux pumps (eg P-glycoprotein) or drug accumulation, FTase activity was markedly reduced in the resistant cell line compared to the parent cell. These results suggest that clinical resistance may develop during FTI treatment.¹⁶⁴ Another recent report showed upregulation of Hsp70 in human ovarian and mesothelioma cells following FTI-treatment, suggesting a cellular mechanism of cell self-protection against apoptosis.¹⁶⁵

Conclusions

Results from clinical trials demonstrate the promising potential of FTIs in myeloid malignancies. Interestingly, responses to FTI treatment do not correlate with the presence of RAS mutations, suggesting that other farnesylated proteins are the relevant molecular targets of FTI. Alternatively, constitutively activated RAS may be relevant as earlier studies demonstrated the sensitivity of human tumor cell lines containing activated RAS.^137,155,166 However, RAS activation has not been reported in correlation with FTI response in patient specimens. The identification of other relevant targets of FTI may elucidate the precise mechanism of action of these drugs and allow development of more specific compounds.

Although all farnesyltransferase inhibitors have been demonstrated to cause myelosuppression, complete remissions can be achieved without severe aplasia. It is currently unclear if FTIs should be utilized in earlier stage disease or as remission maintenance. Additionally, further clinical studies are needed to define which myeloid malignancies (eg AML, CML, CMML, MDS) will best respond to FTI treatment (Table 4).

Table 4 - Currently recruiting phase I and II trials evaluating FTIs in myeloid malignancies.

Full table

Results from a recent phase III clinical trial in pancreatic cancer, which showed no beneficial effect of FTI, seems to support the preclinical observation that alternative cross-prenylation of K- and N-RAS may be an important natural mechanism of resistance. Development of FTIs which more effectively target K- and N-RAS prenylation may overcome this limitation (eg DPIs such as L-778,123). Another option to overcome this alternative prenylation may be the combination of FTIs with other prenylation inhibitors (eg GGTIs, statins and bisphosphonates).

Preclinical studies have demonstrated synergistic cytotoxicity of FTIs in combination with both novel (eg STI571, GGTIs) and conventional chemotherapeutic agents (eg taxanes, topoisomerase II inhibitors, cisplatin).^{96,143,144,147} Currently recruiting and future clinical trials will have to evaluate FTIs in combination regimens with standard chemotherapeutic agents and other targeted therapies (eg STI571) (Table 4). P-glycoprotein (Pgp)-mediated drug efflux causing MDR is a major factor resulting in reduced efficacy of chemotherapy.¹⁶⁷ Many of the standard cancer therapeutics currently used in the treatment of myeloid malignancies are effected by MDR. As FTI SCH66336 has been shown to potently inhibit Pgp, combination regimens with standard cancer chemotherapeutics may be a promising strategy. Additionally, it has recently been demonstrated that SCH66336 induces both synergistic apoptotic responses and overcomes STI571 resistance in CML cells, further supporting the rationale of combining these two targeted therapies.^147,148

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Acknowledgements

We thank Dr Kristine A Henningfeld for critically reading the manuscript. We apologize to those whose contributions have not been cited due to space constraints. This work was supported in part by a grant to CR from Hannover Medical School (HILF-program) a grant to CR from Deutsche Krebshilfe (10-1801-Re1) and a grant to MM from the International Myeloma Foundation.