emerging approaches to target tumor metabolism

Emerging approaches to target tumor metabolismSarah J Ross and Susan E Critchlow

Available online at www.sciencedirect.com

ScienceDirect

Therapeutic exploitation of the next generation of drugs

targeting the genetic basis of cancer will require an

understanding of how cancer genes regulate tumor biology.

Reprogramming of tumor metabolism has been linked with

activation of oncogenes and inactivation of tumor suppressors.

Well established and emerging cancer genes such as MYC,

IDH1/2 and KEAP1 regulate tumor metabolism opening up

opportunities to evaluate metabolic pathway inhibition as a

therapeutic strategy in these tumors.

Addresses

Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire

SK10 4TG, UK

Corresponding author: Critchlow, Susan E

([email protected])

Current Opinion in Pharmacology 2014, 17:22–29

This review comes from a themed issue on Cancer

Edited by Francisco Cruzalegui

http://dx.doi.org/10.1016/j.coph.2014.07.001

1471-4892/# 2014 Published by Elsevier Ltd. All right reserved.

Introduction

The rapid explosion in cancer genome sequencing facili-

tated by next generation sequencing technologies has

transformed our understanding of the genetic basis of a

range of tumors [1]. Mining of this data has confirmed the

importance of known dominant cancer genes such as

BRAF , TP53, EGFR, ERBB2, KRAS, PIK3CA, MYCand VHL but also highlighted a number of genes that

were not previously suspected to drive cancer such as

KEAP1, IDH1/2, RAC1 and MYD88 [2]. The dominant

role that mutated cancer genes play in driving tumorigen-

esis has been exploited in modern Oncology therapies

with several transformational examples. The paradigm

was defined through the development of imatinib that

inhibits the BCR-ABL driver tyrosine kinase in chronic

myeloid leukemia (CML) [3] with several subsequent

examples including targeting mutant EGFR in lung

cancer [4], mutant V600E BRAF mutations in melanoma

[5] and ALK in non-small cell lung cancer with ALK gene

rearrangements [6,7�]. These set an exciting precedent

for the next generation of cancer medicines that exploit

the genetic basis of cancer.


Exploiting the therapeutic potential of emerging and/or

intractable cancer genes will require a step-change in our

understanding of the key biological pathways driven by

these genes, innovations in drugging new target classes

and novel targeting strategies. One of the emerging areas

of cancer biology that has been recognized as an emerging

‘hallmark of cancer’ is the reprogramming of tumor

metabolism to fuel cell growth and proliferation [8].

Several metabolic pathways have been implicated in

the metabolic reprogramming observed in tumors in-

cluding increased flux through the glycolysis, glutamine

and pentose phosphate pathways, increased rates of lipid

synthesis and maintenance of redox balance [9]. Target-

ing tumor metabolism to identify new cancer therapies

has received renewed interest [10��]. One of the chal-

lenges of direct targeting of metabolic pathways is the

potential for a detrimental effect on normal tissues that

also rely on these pathways. However, emerging data is

demonstrating how cancer genes drive specific metabolic

pathway dependencies creating the opportunity to target

these pathways and minimize the effect on normal tis-

sues. In this article we will describe emerging data linking

cancer genetics with cancer metabolism, highlighting

where this data is opening up new therapeutic opportu-

nities.

Isocitrate dehydrogenase mutations inleukemia and gliomaGenomic approaches have revealed new and unantici-

pated target opportunities. For example, the systematic

sequencing of glioblastoma multiforme (GBM) genomes

has identified the recurrent mutation of IDH1, a gene

encoding NADP(+)-dependent isocitrate dehydrogenase

1 that normally catalyses the oxidative decarboxylation of

isocitrate to give alpha-ketoglutarate (a-KG) in the tri-

carboxylic acid (TCA) cycle [11]. Subsequent studies

identified specific mutations in IDH1 and IDH2 occurring

in glioma, most commonly in patients with low-grade

glioma [12] and in 15–30% of acute myelogenous leuke-

mias (AML) [13]. Intriguingly, the specific mutations in

IDH1 and IDH2 cause a gain-of-function activity result-

ing in conversion of isocitrate to R-2-hydroxyglutarate

(2-HG) [14�,15]. Ground-breaking studies have eluci-

dated the primary mode of action of the 2-HG ‘oncome-

tabolite’. 2-HG was hypothesized to competitively inhibit

the activity of a broad spectrum of a-KG-dependent

enzymes. Mutational and epigenetic profiling of a large

AML patient cohort revealed that IDH1/2-mutations

display DNA hypermethylation and that expression of

2HG-producing IDH alleles in cells induce global

DNA hypermethylation [16]. Furthermore, in AML

patients, IDH1/2 mutations were mutually exclusive with

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Emerging approaches to target tumor metabolism Ross and Critchlow 23

inactivating mutations in TET2 — a gene encoding an a-

KG-dependent dioxygenase that converts 5-methylcyto-

sine (the biochemical mark of DNA methylation) into 5-

hydroxymethylcytosine. These data suggested that IDH1or IDH2 and TET2 mutations may be functionally redun-

dant. In support of this hypothesis, expression of mutant

IDH1/2 or Tet2 depletion was found to impair hemato-

poietic differentiation mediated in part through 2-HG

inhibition of TET2 DNA demethylation activity [16].

Other studies have confirmed that 2-HG inhibits other a-

KG-dependent enzymes including Jumonji-C domain

histone demethylases [17] and prolyl-4-hydroxylases that

regulate hypoxia induced factor HIF [18] (Figure 1a).

The IDH1/2 example represents a novel and unantici-

pated link between cancer gene mutation, cancer metab-

olism and regulation of gene expression and cellular

differentiation raising new avenues for cancer drug dis-

covery. Building on the kinase precedent, drug discovery

efforts have been directed to the identification of mutant

IDH1 or mutant IDH2 selective inhibitors. For example,

Wang et al. [19] have developed AGI-6780, a potent,

selective and novel allosteric inhibitor of the most com-

monly occurring IDH mutation in AML, IDH2(R140Q).

AGI-6780 displays greater than 10-fold selectivity over

wild-type IDH2 and excellent selectivity against other

dehydrogenases, including the closely related wild-type

IDH1 or the IDH1(R132H) mutant. Treatment of an

erytholeukemia cell line ectopically expressing IDH2-

R140Q with AGI-6780 reduced 2-HG levels and induced

differentiation. Further studies demonstrated that treat-

ment of primary human IDH2(R140Q) mutant AML cells

with AGI-6780 induced differentiation of the AML blasts

through the macrophage and granulocyte lineages [19]. In

parallel, inhibitors of the most commonly occurring IDH1

mutation in glioma have been developed [20]. Selective

inhibition of IDH1(R132H) with AGI-5198 also reduces

2-HG levels with a concurrent inhibition of soft agar

growth of the TS603 glioma cell line. Furthermore,

AGI-5198 caused a �50–60% inhibition of tumor xeno-

graft growth in vivo. Additional biomarker studies demon-

strated that treatment of xenografts with the mutant-

selective IDH1(R132H) inhibitor induced demethylation

of histone H3K9me3 and expression of genes associated

with glial differentiation [20]. Taken together, these

studies suggest that selective inhibitors of IDH1 and

IDH2 may have therapeutic potential in glioma and

AML.

Several questions remain that will be key in understand-

ing the therapeutic value of mutant-selective IDH1/2

inhibitors. The emerging inhibitors appear to have a

cytostatic rather than pro-apoptotic profile raising ques-

tions on whether IDH1/2 monotherapy will give durable

responses in the clinic. The major phenotypic response

following treatment of glial/AML cells with IDH1/2

inhibitors is an induction of cellular differentiation


through epigenetic reprogramming and it remains to be

determined whether the effects of 2-HG are reversible in

the clinic. Recent data from Losman et al. demonstrates

that in preclinical models the effects of 2-HG are revers-

ible [21]. In other studies the presence of known cancer

driver gene aberrations in IDH1-mutant glioma has been

assessed. Mutations in PIK3CA, KRAS, AKT or PTEN or

PDGFR, MET or N-MYC amplifications were detected in

13.4% of IDH-mutant glioma patients [22]. Further stu-

dies will be required to understand the impact of co-

occurring mutations on sensitivity to IDH1-selective

inhibitors and whether combination therapy will be

required with agents targeting these additional genetic

lesions. Significantly, clinical responses have been

observed in the first clinical trials assessing the safety

and tolerability of AG-221 in AML patients. Six out of

seven evaluable patients have been reported to have

objective responses, including three complete remissions

(CR) and two complete remissions with incomplete pla-

telet recovery. Consistent with the expected mode of

action, AG-221 is reported to lower plasma levels of the

oncometabolite 2-HG in the Phase 1 trial (http://inves-

tor.agios.com/phoenix.zhtml?c=251862&p=irol-newsAr-

ticle&ID=1916041&highlight=). This exciting clinical

data raises the hope that the ‘kinase’ paradigm can be

extended to other genetic targets that are involved in

tumor metabolism.

Targeting the metabolic phenotype of cMyc-dependent tumorsDeregulated c-Myc expression through amplification or

gene translocation has been identified in many human

cancers including breast, prostate, colon, bladder cancer

and a range of hematological tumors [23]. c-Myc was

initially identified as the target oncogene dysregulated

by the t(8;14)(q24;q32) translocation in Burkitt lym-

phoma [24]. In addition, 5–15% of diffuse large B-cell

lymphomas (DLBCL) have been reported to carry MYCtranslocations [25]. c-Myc is a helix–loop–helix transcrip-

tion factor that regulates the expression of a large range of

genes involved in cell cycle control, cell growth and

cellular metabolism [23]. N-Myc also belongs to the

Myc family of transcription factors and is amplified in a

range of tumor types, most notably in �20% of neuro-

blastoma and 15–20% of small cell lung cancers (SCLC).

N-Myc amplification is often associated with poor prog-

nosis [26�]. Because of structural and sequence homology

between the Myc family genes, the functional properties

of Myc proteins are closely related. c-Myc and N-Myc can

functionally replace one another in the appropriate con-

text and share similar oncogenic properties. However,

they appear to be exclusively over-expressed in different

tumor types, suggesting that they have independent and

tissue-specific roles [26�].

Given c-Myc’s role as a master controller of cellular

growth and frequent over-expression/activation in a range


http://investor.agios.com/phoenix.zhtml?c=251862&p=irol-newsArticle&ID=1916041&highlight=



24 Cancer

Figure 1

Cys-X

NRF2

Glutamine

(a)

Myc

TCAcycle

Mitochondria

Glucose

Lactate

MCT1

GLUT1

ASCT2

Glucose-6P

HK2

Pyruvate LactateLDHA

Glutamine

GLS

miR23a/b

Glu

Glutamine

Basal conditionsNRF2 degraded

Oxidative stressNRF2 activated

CUL3

KEAP1

KEAP1

Nucleus

Ub

Ub

Proteosomal degradationof NRF2

Ubiquitinylation

No gene transcription

ARE

KEAP1

NRF2KEAP1

Nucleus Gene transcription

ARE

NRF2NRF2

NRF2

KEAP1 inactivatedNRF2 translocates to the nucleus

Cys residues withinKEAP1modified

CUL3

CUL3

CUL3

Antioxidant proteinsDrug efflux pumpsMetabolic genesDrug metabolizing enzymes

MitochondriaNucleus

TCAcycle

Citrate

Isocitrate

α-KG

2-HG

Citrate

Isocitrate

α-KG

2-HG

HIF1α

IDH2

IDH1 TET2

Histonedemethylase

Dysregulatedgene expression

IDH2mut

IDH1mut

(b)

(c)

Current Opinion in Pharmacology

Current Opinion in Pharmacology 2014, 17:22–29 www.sciencedirect.com


of tumors, c-Myc is viewed as an attractive therapeutic

target in cancer [27]. However, c-Myc is a transcription

factor and direct targeting of c-Myc is likely to be chal-

lenging [26�]. An alternative strategy that has been pro-

posed to target Myc-dependent tumors is to inhibit the

metabolic pathways that are driven by c-Myc [23,28��]. A

multitude of studies have implicated c-Myc as a major

regulator of tumor metabolism (reviewed in [23,28��]). c-

Myc has been shown to regulate the expression of a

number of glucose metabolism genes including LDHA,

GLUT1, HK2, PFKM, ENO1 and SLC16A1 (gene encod-

ing MCT1) stimulating glycolytic flux in tumor cells

[23,28��,29]. c-Myc also stimulates mitochondrial bio-

genesis and regulates the expression of nuclear-encoded

mitochondrial genes [30]. Recent studies have demon-

strated that Myc also regulates glutamine metabolism

through direct and indirect activation of genes involved

in glutamine uptake and metabolism [31,32] (Figure 1b).

Glutamine is an important source of nitrogen for biosyn-

thesis and a carbon source to replenish tricarboxylic acid

(TCA) cycle intermediates that have been extracted for

biosynthesis (a process known as anapleurosis). Targeting

these metabolic pathways could open new avenues to

treat Myc-driven tumors and we will outline key progress

in developing inhibitors of Myc-driven metabolic path-

ways.

A number of lines of evidence support a direct link

between Myc driving the glycolytic phenotype of tumors

and lactate dehydrogenase A (LDHA). LDHA regulates

the conversion of pyruvate to lactate as part of the

glycolytic pathway. LDHA is a direct Myc target gene

and Myc-transformed cells produce more lactate than

control cells [33]. Furthermore, Myc transgenic animals

that overexpress c-Myc in the liver, show increased

glycolytic enzyme activity in the liver and overproduce

lactate [34]. Other studies have demonstrated that

shRNA knockdown of LDHA expression in tumor cell

lines decreases proliferation under hypoxic conditions

[35]. Taken together, these data support LDHA as a

potential target to inhibit the growth of Myc-driven

glycolytic tumors. In the last few years, a number of

LDHA inhibitors have been identified by fragment-based

lead generation [36,37] or high-throughput screening

[38–40]. Encouragingly, some of these inhibitors have

been demonstrated to decrease lactate production in

cellular systems [36,37,40]. Billiard et al. have identified

(Figure 1 legend) (a) Regulation of epigenetics by 2-hydroxyglutarate. Muta

function enzymatic activity resulting in the conversion of a-KG into 2-hydrox

display increased levels of 2-HG, which inhibits a number of a-KG-depende

metabolite 2-HG inhibits the TET2 hydroxymethylase, decreasing levels of 5

levels of 2-HG and a-KG in IDH1 and IDH2 mutant tumors contributes to abe

by cMyc. Myc regulates genes involved in glycolysis and glutaminolysis. My

(GLUT1, HK2, LDHA, MCT1 and PDHK1) driving the conversion of glucose to

of glutamine transporters and glutaminase (GLS1). (c) The Keap1–Nrf2 signal

and acts as an adaptor for the Cul3 E3 ubiquitin ligase that targets Nrf2 for

residues within KEAP1 are modified, releasing Nrf2 to translocate to the nuc

control of an Antioxidant Response Element (ARE).


potent LDHA inhibitors that display selectivity over

LDHB, potently inhibit lactate production across a panel

of cell lines and demonstrate anti-proliferative activity

[40]. It remains to be determined whether these small

molecules inhibit the growth of Myc-driven tumors and

whether they can be optimized to in vivo probes and/or

clinical candidate drugs.

Lactate produced by high glycolytic flux in tumor cells is

exported out of the cell via the proton-dependent mono-

carboxylate transporters (MCTs). MCT1 and MCT4 are

the key tumor-associated lactate transporters and

represent an alternative strategy to target the glycolytic

phenotype of tumors [41]. Recent data has confirmed that

Myc regulates SLC16A1 (MCT1) and LDHA expression

in the Em-Myc transgenic mouse model of human B

lymphoma [29]. Functional and chromatin immunopre-

cipitation studies have confirmed that MCT1 is a direct

Myc transcriptional target in normal and tumor cells [29].

Furthermore, concomitant high levels of MCT1 and MYCmRNA are observed in Burkitt lymphoma, and of MCT1and MYCN in MYCN-amplified neuroblastoma [29].

MCT1 inhibitors have been developed [42] and inhibit

the growth of tumor cell lines in vitro and tumor xeno-

grafts in vivo [43,44]. Inhibition of MCT1 decreased the

proliferation of the Raji Burkitt lymphoma cell line invitro and inhibited Raji xenograft growth in vivo. Other

studies have evaluated the activity of MCT1 inhibitors in

SCLC, an alternative tumor setting where frequent MYCamplifications are observed. The MCT1 inhibitor,

AZD3965, decreased the proliferation of SCLC cell lines

and inhibited growth of the COR-L103 xenograft model

in vivo [43]. In both studies, an alternative lactate trans-

porter, MCT4, was identified as a potential resistance

factor to MCT1 inhibition [29,43]. Together, these stu-

dies suggest that inhibition of the MCT1 lactate trans-

porter could be a promising strategy to target Myc-

dependent tumors. Clinical trials on the MCT1 inhibitor,

AZD3965, have been initiated [http://www.clinicaltrials.-

gov/ct2/show/NCT01791595].

In addition to regulating the expression of glycolytic

genes, c-Myc regulates the expression of genes that

control glutamine metabolism [32]. Myc activates the

transcription of the glutamine transporter ASCT2 in

glioma cell lines and knockdown of Myc reduces gluta-

mine consumption in glioma cell lines [31]. Proteomic

nt IDH1 (cytoplasmic) and IDH2 (mitochondrial) enzymes show a gain-of-

yglutarate (2-HG), an oncometabolite. IDH1 and IDH2 mutant tumors

nt enzymes involved in epigenetic regulation and HIF signaling. The

-hydroxymethylcytosine. The epigenetic dysregulation caused by altered

rrant regulation of gene expression. (b) Regulation of tumor metabolism

c regulates the expression of genes involved in glucose metabolism

lactate. Myc also regulates glutamine metabolism through the regulation

ing pathway. In basal conditions, Keap1 sequesters Nrf2 in the cytoplasm

proteasomal degradation. On exposure to oxidative stress, cysteine

leus and activate the transcription of cytoprotective genes under the


http://www.clinicaltrials.gov/ct2/show/NCT01791595


26 Cancer

studies of mitochondria from human P-493 B cells over-

expressing Myc demonstrated that mitochondrial gluta-

minase (GLS1) was induced >10-fold by Myc [32]. GLS1

is the first enzyme that converts glutamine to glutamate,

which is in turn converted to a-ketoglutarate to feed the

TCA cycle. Further analyses revealed that the ASCT2

and SLC7A25 glutamine transporters are also direct Myc

target genes. Interestingly, in addition c-Myc regulates

glutamine metabolism by transcriptionally repressing the

miRNAs, miR-23a and miR23b [32]. miR23a/b targets the

30-UTR of GLS1 leading to loss of GLS1 expression. This

data supports a model where c-Myc suppression of miR-

23a/b enhances GLS1 expression and glutamine metab-

olism [32]. Mouse transgenic models have also demon-

strated that MYC-induced liver tumors displayed

increased glutamine metabolism associated with a switch

from GLS2 to GLS1 glutaminase and a reduction in

glutamine synthetase expression [45]. Other metabolic

tracer and proliferation studies in a MYC-inducible P493

Burkitt lymphoma model have demonstrated that gluta-

mine metabolism is essential under hypoxic conditions

[46]. The novel GLS1 inhibitor, BPTES [47], inhibits the

growth of P493 cells under aerobic conditions and induces

cell death under hypoxic conditions [46]. Furthermore,

BPTES reduces the growth of P493 xenografts in vivo[46]. Recent studies have identified a more potent glu-

taminase inhibitor CB-839 [48]. CB-839 inhibited gluta-

mine metabolism and demonstrated potent anti-

proliferative activity against a panel of triple-negative

breast cancer (TNBC) cell lines. Furthermore, CB-839

displayed significant anti-tumor efficacy in a patient-

derived TNBC model [48] supporting further clinical

development of glutaminase inhibitors [http://www.clini-

caltrials.gov/show/NCT02071862].

Over the last 3 years encouraging progress has been made

to develop several inhibitors of Myc-driven metabolic

pathways. Whilst emerging data demonstrates that these

inhibitors delay tumor growth in preclinical models, it will

be important to evaluate clinical efficacy in Myc-driven

tumors and to build an understanding of how to select

patients where Myc is driving the metabolic phenotype of

the tumor.

Emerging role of the Keap1/Nrf2 pathway incancerComprehensive genome profiling projects have high-

lighted the importance of other previously under-appreci-

ated tumor-associated pathways. For example,

characterization of the genomic and epigenomic profile

of 178 lung squamous cell carcinomas has highlighted that

targets of the Keap1–Nrf2 oxidative stress response path-

way are frequently mutated [49]. Previous studies had

identified loss-of-function mutations in the KEAP1 gene

in lung cancer cell lines and in non-small cell lung cancer

(NSCLC) tumor samples [50]. The Kelch-like-ECH-

associated protein 1 (KEAP1) controls the activation of


the nuclear factor erythroid-2 related factor 2 (NRF2)

transcription factor. Keap1 functions as a sensor to oxi-

dative stress and in the absence of stress sequests Nrf2 in

the cytoplasm of cells and acts as an adaptor for the Cul3

E3 ligase that targets Nrf2 for proteasomal degradation

[51]. On exposure to oxidative stress, Keap1 is modified,

releasing Nrf2 to translocate to the nucleus and activate

the transcription of a range of cytoprotective genes

[52,53��] (Figure 1c). Initial studies systematically ana-

lyzing the KEAP1 genome locus in lung tumors and cell

lines revealed a range of deletion, insertion and missense

mutations within highly conserved regions in the Kelch

domains of the Keap1 protein suggesting that mutations

abolish Keap1 repressor activity. Furthermore, frequent

loss of heterozygosity was observed at the KEAP1 geno-

mic locus 19p13.2 [50]. The comprehensive genome

studies have provided an additional layer of somatic copy

number alteration data in addition to mutation data. This

has revealed that in 34% of squamous lung carcinoma

cases there are mutations and copy number alterations of

KEAP1 and NFE2L2 (Nrf2 gene) and/or deletion or

mutation of CUL3 [49]. Taken together, genome charac-

terization data supports that the Keap1–Nrf2 pathway is

frequently altered in tumors. Indeed, pathway aberrations

have been reported across multiple tumor indications

including ovarian and clear-cell renal carcinoma, head

and neck cancer, hepatocellular and gastric cancer and

melanoma [54�,55,56].

Multiple studies have confirmed that loss of Keap1 acti-

vates Nrf2 leading to nuclear accumulation and transcrip-

tional induction of target genes (reviewed in [50,53��]).Consistent with the role of the Keap1–Nrf2 pathway in

mediating a cytoprotective program in response to oxi-

dative stress and drug toxicity, the target genes of Nrf2

include genes involved in the regulation of glutathione,

genes for anti-oxidant proteins, drug metabolizing

enzymes and transporters and metabolic genes [53��].Nrf2 regulates the metabolic phenotype of tumors

through regulating the expression of several components

on the Pentose Phosphate Pathway (PPP) and NADPH

production pathway that provides intermediates for the

synthesis of nucleic acids, amino acids, and lipid syn-

thesis — important for supporting increased tumor cell

proliferation [57��]. The importance of the PPP pathway

in Nrf2-overexpressing cells was confirmed by knocking-

down G6PD and TKT, which are involved in the oxidative

and non-oxidative arms of the PPP. Simultaneous knock-

down of G6PD and TKT inhibited tumor growth of a

KEAP1 mutant cell line in vivo. These data suggest that

direct targeting of metabolic pathways could have poten-

tial in treating tumors with a dysregulated Keap1–Nrf2

pathway.

In order to validate the Keap1–Nrf2 pathway in lung

cancer, various groups have performed RNAi-mediated

silencing approaches to evaluate the role of Nrf2 on the


http://www.clinicaltrials.gov/show/NCT02071862

http://www.clinicaltrials.gov/show/NCT02071862


growth and survival of lung cancer models. Nrf2 shRNA-

mediated knock-down reduces growth of KEAP1 mutant

lung cell lines in vitro and xenograft models in vivo[57��,58]. Furthermore, activation of the Keap1–Nrf2

pathway causes increased expression of genes involved

in drug metabolism and activation of the pathway has

been associated with chemo-resistance [52,59]. Indeed,

Nrf2 knock-down suppresses cell proliferation and resist-

ance of lung cancer cell lines to cisplatin and sensitizes a

cervical cancer cell line to chemotherapeutic drugs in vitroand in vivo [60,61]. However, Nrf2 has also been shown to

have tumor suppressor functions by increasing the

expression of cytoprotective genes. For example, studies

of Nrf2-deficient mice have shown that Nrf2 protects

from carcinogen-induced tumor formation in the stomach,

skin and bladder and this and other studies support the

hypothesis that Nrf2 may be cytoprotective in normal

tissues [62]. The high prevalence of Keap1–Nrf2 geneti-

cally driven pathway activation in multiple tumors, and

role of Nrf2 in driving chemo-resistance, supports the

hypothesis that inhibiting the Nrf2 pathway will be an

important therapeutic approach. It is currently unclear

whether targeting specific Nrf2-driven metabolic adap-

tations with small molecule inhibitors will inhibit the

growth of tumors with defects on the Keap1–Nrf2 path-

way. Additional target validation and drug discovery/

therapeutic targeting strategies are warranted against this

pathway.

Progress on direct targeting of undruggablecancer genesAside from targeting the metabolic dependence driven by

key cancer driver genes such as Myc, several alternative

targeting strategies are being developed that could enable

direct targeting of these targets or downstream pathways.

This may be crucial for targets with lower druggability

such as transcription factors and/or metabolic targets.

Advances in oligonucleotide based therapies, predomi-

nantly antisense oligonucleotides (ASOs) and small inter-

fering RNAs (siRNAs), are bringing into scope oncology

targets such as transcription factors that have proved

undruggable through conventional drug discovery

approaches. The concept of antisense and siRNA is

similar in that for both a complementary synthetic oligo-

nucleotide binds specifically to a target RNA of interest

and inhibits its expression or function [63]. Chemical

modifications have been key in significantly improving

oligonucleotide stability, potency and specificity and

making these molecules more drug-like. In parallel deliv-

ery platforms for efficient systemic delivery have been

explored enhancing tissue delivery and cellular uptake of

oligonucleotides [63,64].

Recent data has demonstrated that a dicer substrate

siRNA targeting MYC could effectively reduce target

mRNA and protein expression in mouse tumor models


in vivo when delivered to the tumor using a lipid nano-

particle (LNP) delivery system leading to inhibition of

tumor growth [65]. Following this encouraging preclinical

data MYC siRNA in a stable lipid particle (DCR-MYC)

has just entered phase I clinical trials in solid and hem-

atological tumors [http://www.clinicaltrials.gov/ct2/show/

NCT02110563].

ConclusionsThe last decade has seen the successful clinical trans-

lation of actionable driver kinases in Oncology. While

targeting tumor metabolism has emerged as a novel area

of cancer drug discovery, it is anticipated that successful

translation into clinical activity will require an equivalent

addiction to a specific metabolic pathway. New data

demonstrating that activation of oncogenes and/or inac-

tivation of tumor suppressor genes leads to specific meta-

bolic reprogramming, supports the hypothesis that

targeting tumor metabolism can be a valuable therapeutic

strategy in Oncology. The next generation of drugs

targeting metabolism are now entering clinical develop-

ment and the resultant clinical data will help inform new

strategies to target cancer genes.

Conflict of interestSJR and SEC are AstraZeneca employees and stock-

holders.

AcknowledgementsWe would like to thank Steve Durant for helpful comments on themanuscript. We would also like to acknowledge the authors of numerousrelevant papers that could not be cited due to space constraints.

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emerging approaches to target tumor metabolism

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