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Authors’ Affi liations: 1 University of Turin, Department of Oncology, Can-diolo (TO); 2 IRCC, Institute for Cancer Research and Treatment at Candiolo, Candiolo (TO); 3 FIRC Institute of Molecular Oncology (IFOM), Milan, Italy.

Corresponding Author: Alberto Bardelli, University of Turin, Department of Oncology, IRCC, Institute for Cancer Research and Treatment at Can-diolo, SP 142, Candiolo, Torino 10060, Italy; Phone: 39-11-993-3235; Fax: 39-11-993-3225; E-mail: alberto.bardelli@unito.it

doi: 10.1158/2159-8290.CD-13-0906

©2014 American Association for Cancer Research.

IN THE SPOTLIGHT

Climbing RAS, the Everest of Oncogenes Mariangela Russo 1 , 2 , Federica Di Nicolantonio 1 , 2 , and Alberto Bardelli 1 , 2 , 3

Summary: Mutations that activate the small GTP-binding protein KRAS are the most common oncogenic event

in human tumors. Thirty years after its discovery, mutant KRAS has yet to be therapeutically conquered. Cancer

Discov; 4(1); 19–21. ©2014 AACR.

See related article by Faber et al., p. 42 (1).

The genomic landscape of human cancers contains few

mountains (genes mutated at high frequency) and thou-

sands of small hills (genes mutated at low frequency). In this

landscape, KRAS is by far the tallest oncogenic peak. With its

overwhelming 8,848 meters, Everest is the highest mountain

on the earth’s surface. The challenges of tackling mutant

KRAS and climbing Everest display noteworthy analogies.

For decades, even the most experienced hikers thought that

Everest was impossible to conquer. Subsequent generations

of climbers challenged this assumption. Several expeditions

then started to besiege (literally) Everest from its fl anks. The

competition was fi erce and the initial attempts failed, some

with fatal consequences. Eventually, however, Everest was

successfully conquered in 1953. Key factors to this landmark

success were meticulous planning, technological resources,

teamwork, bravery, and resilience, but above all, the lessons

learned from previous failed attempts. Similar elements are

needed to develop anti-KRAS treatments. Although we have

yet to “therapeutically conquer” mutant KRAS, research car-

ried out in recent years, including the study by Faber and

colleagues ( 1 ) described in this issue of Cancer Discovery , has

brought us closer to the summit.

Mutations of the GTPase protein KRAS, the principal of

the three isoforms of RAS, occur in approximately 20% of all

cancers and are particularly prevalent in malignancies with

the highest mortality rates, such as pancreatic (90%), colorec-

tal (40%), and lung (25%) tumors ( http://cancer.sanger.ac.uk/

cancergenome/projects/cosmic/ ). By impairing the intrinsic

GTPase activity, KRAS mutations are responsible for maintain-

ing the protein in a constitutively active GTP-bound state ( 2 ).

Mutations in KRAS were fi rst reported in 1982 and are

associated with poor prognosis and resistance to therapy.

Thirty years after its discovery, mutant KRAS still poses

a formidable challenge to researchers and clinicians alike

as attempts to directly target this small (21 kDa) protein

have, so far, failed ( 2 ). For this reason, direct pharmacologic

blockade of KRAS is often viewed as an impossible mission.

As for Everest, a few scientists have started to challenge this

assumption and innovative approaches appear to be promis-

ing ( 3, 4 ).

Although direct assaults on KRAS itself are being refi ned,

many groups approached the problem from a different per-

spective and decided to besiege mutant KRAS at its fl anks.

The latter are downstream effectors in the cellular pathways

initiated by KRAS, which act as a master switch in the pro-

liferation of mammalian cells. Divergent tactics have been

deployed to identify factors essential for the survival and

growth of cells harboring KRAS mutations, including syn-

thetic lethality approaches, pharmacologic strategies, or the

combination of both.

Genetic-based screens spawned a list of genes, including

TBK1, STK33, PLK1 , and more recently TAK1 , whose suppres-

sion was found to be synthetically lethal with KRAS mutations

( Fig. 1 ; refs. 2 , 5 ). Notably, overlaps among candidates identi-

fi ed by these studies are modest and, so far, none of these hits

has translated into effective therapies in the clinical setting.

Preliminary attempts at targeting single effectors down-

stream of KRAS (e.g., PI3K and MEK) showed modest or no

effi cacy, especially in colorectal tumors ( 6, 7 ), likely because

KRAS activates multiple parallel networks, such as the MEK–

ERK, PI3K–AKT, and NF-κB pathways (refs. 2 , 8 , 9 ; Fig. 1 ).

Combinatorial strategies embracing concomitant inhibi-

tion of KRAS effectors were then proposed. Among these, the

blockade of MEK and PI3K induced regression in a KRAS-

driven mouse model of lung cancer ( 10 ). Unfortunately,

the toxicity of this combination appears to limit its clinical

applicability. Alternative strategies involve targeting MEK

together with receptor tyrosine kinases, including IGF-IR ( 11 )

or HER3 ( Fig. 1 ; ref. 8 ).

In this issue of Cancer Discovery , Faber and colleagues ( 1 )

propose an alternative combinatorial approach to inhibit

KRAS -mutant colorectal cancer cells. Leveraging previous

high-throughput screenings that assessed the sensitivity of

a collection of more than 600 tumor-cell lines to 130 drugs,

they found that KRAS -mutated colorectal cancer cells were

selectively affected (as compared with wild-type) by coinhibi-

tion of three members of the antiapoptotic family: BCL-2,

BCL-XL, and MCL-1.

Previous work by the same authors showed that targeting

BCL-2 and BCL-XL with a BH3 mimetic molecule, named

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ABT-263, is not suffi cient to induce apoptosis in KRAS -mutated

cells ( 12 ). The current study indicates that concomitant sup-

pression of MCL-1 is required to sensitize KRAS -mutant

colorectal cancer cells to ABT-263. They report that a single

compound, obatoclax, could achieve the triple inhibition of

MCL1, BCL2, and BCL-XL. However, the clinical toxicity of

this molecule (likely associated with off-target effects) limits

its exploitation. To suppress MCL-1 more selectively, Faber

and colleagues ( 1 ) therefore employed AZD8055, a TORC1/2

inhibitor, which was found to reduce the translation of MCL1

mRNA in a genotype-selective fashion. When targeting of

BCL-2/BCL-XL (with ABT-263) and suppression of MCL-1

(by AZD8055) were combined, KRAS -mutant cells, differ-

ently from their wild-type counterparts, underwent apoptosis.

Remarkably, this combinatorial regimen was equally effective

in mouse xenografts and in a genetically engineered mouse

model of colorectal cancer driven by mutant KRAS ( 1 ).

Although this study is a step forward toward the “thera-

peutic conquering” of mutant KRAS, it also raises several

questions.

As discussed above, this is not the fi rst report to pinpoint a

cocktail of drugs that selectively target cells carrying mutant

KRAS. Some of the previous fi ndings in this area proved to

be less broadly applicable than initially thought. We pro-

pose that the intrinsic heterogeneity of KRAS -mutant tumors

could account for the modest success achieved so far.

First, heterogeneity can result from oncogenic variants

that affect distinct codons of KRAS (12, 13, 61, 117, and

146) or that translate in different amino-acid changes on the

same codon. All these mutations might engage with differ-

ent signaling assets, some of which have just emerged ( 13 ).

Second, KRAS mutations occur within the given mutational

architecture of the genome; how diverse genetic backgrounds

can affect the biochemical and biologic behavior of activated

KRAS is largely unexplored. Third, depending on the tis-

sue of origin, different feedback loops can be activated in

response to inhibition of effectors of the KRAS pathway ( 8 , 14 ).

Finally, it is often believed that all KRAS -mutant tumors

are uniformly “addicted” to this genetic alteration. Indeed,

a recent report noted that the presence of KRAS-activating

Figure 1.   Strategies to tackle KRAS -mutant tumors. Mutant KRAS is the tallest oncogenic peak in the cancer genome landscape, with about 1 million new cases of KRAS -mutant cancer every year ( http://www.wcrf.org/cancer_statistics/world_cancer_statistics.php ). Since its discovery, over 30 years ago, mutated KRAS has remained therapeutically unconquered. The fi gure summarizes strategies proposed so far to defeat tumor cells bearing KRAS muta-tions: (1) direct inhibition of KRAS posttranslational modifi cations (indicated in blue); (2) direct inhibition of KRAS (indicated in purple); (3) identifi cation of cellular factors whose blockade is synthetically lethal with the presence of KRAS -mutant alleles (indicated in green); and (4) pharmacologic inhibition of signaling effectors regulated by mutant KRAS (depicted in orange).

BASE CAMP Discovery of mutated RAS

CAMP-7 KRAS direct inhibitors

CAMP-3 KRAS synthetic lethal

candidates CAMP-5 MEK + IGF-IR

CAMP-8 MEK + BCL-2/BCL-XL

CAMP-9 TORC + BCL-2/BCL-XL

CAMP-2 KRAS single effectors

BRAF, MEK, and PI3K

CAMP-4 MEK + PI3K

Mount KRAS ~1 × 106 cases per year

CAMP-6 MEK + HER3

CAMP-1 KRAS posttranslational

modifications

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mutations does not necessary imply KRAS dependency of

the tumor to maintain viability ( 15 ), which suggests that

KRAS -mutant cancers could be further subclassifi ed accord-

ing to their addiction.

All these factors are likely to contribute to the biochemical,

biologic, and clinical heterogeneity of KRAS -mutant cancers,

thus explaining why a specifi c drug mix may be effective only

in a subset of KRAS -mutated tumors. Related to this is the

authors’ fi nding that the ABT-263–AZD8055 combinato-

rial treatment is much less effective on KRAS -mutant lung

cancer cells ( 1 ). Clearly, additional work is warranted to

establish the effi cacy of TORC–BCL combined inhibition on

KRAS -mutant tumors of different histologic origins. If KRAS -

mutated tumors are indeed, as we believe, a heterogeneous

population, it will be of utmost importance to defi ne biomar-

kers that can guide their (sub)classifi cation. As genetics is

unlikely to be of further help, transcriptional and biochemi-

cal signatures may become decisive to predict the subsets of

KRAS -mutant cancers that will preferentially benefi t from a

given combinatorial therapy.

Finally, it remains undefi ned whether the preclinical activity

of ABT-263 in combination with TORC inhibitors is superior to

other combinatorial strategies previously devised to target lung,

pancreatic, or colorectal KRAS -mutated tumors. Comparative

studies are needed to test side by side the most effective drug

cocktails. Ideally, these studies should be performed in large

collections of cell lines and/or patient-derived xenografts.

Notwithstanding the above issues, the results presented

in this issue of Cancer Discovery represent an important step

forward, as they reveal a nonconventional drug regimen for

some of the most recalcitrant tumors. As both ABT-263 and

AZD8055 have entered clinical development as single agents,

their combination could then be tested in KRAS -mutant

colorectal cancers. As these compounds (especially ABT-263)

display prominent intrinsic toxicities, clinical experimenta-

tion will be challenging.

So, where do we stand on the climb of mutant KRAS, the

Everest of oncogenes? Multiple expeditions performed in

cells and mouse models led us encouragingly forward. As a

result, several drug combinations, allegedly KRAS -mutant

selective, are now undergoing clinical validations, which will

eventually determine their merit.

Experienced climbers know that the most evident track,

devised from base camp, can often be deceiving; once one gets

closer to the summit, the solution then becomes apparent,

sometimes even obvious. Therapeutic conquering of mutant

KRAS will require further nonconventional thinking and dar-

ing. As with all journeys that are originally considered impos-

sible, success will be highly gratifying.

Disclosure of Potential Confl icts of Interest No potential confl icts of interest were disclosed.

Grant Support Research in the authors’ laboratories is supported by Fondazi-

one Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2010

Ministero della Salute; AIRC 2010 Special Program Molecular Clini-

cal Oncology 5xMille, Project n.9970 (to A. Bardelli); Ministero

dell’Istruzione, dell’Università e della Ricerca (progetto PRIN);

AIRC, grants IG 12812 (to A. Bardelli) and MFAG 11349 (to F. Di

Nicolantonio); Progetti di Ateneo-2011, Università di Torino (codice

ORTO11RKTW); the European Community’s Seventh Framework

Programme under grant agreement n.259015 COLTHERES; Fon-

dazione Piemontese per la Ricerca sul Cancro, ONLUS grant Farma-

cogenomica, 5 per mille 2009 MIUR (to F. Di Nicolantonio).

Published online January 8, 2014.

REFERENCES 1. Faber AC , Coffee EM , Costa C , Dastur A , Ebi H , Hata AN , et al.

mTOR inhibition specifi cally sensitizes colorectal cancers with KRAS

or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing

MCL-1 . Cancer Discov 2014;4:42–52 .

2. Cox AD , Der CJ . Ras history: the saga continues . Small GTPases

2010 ; 1 : 2 – 27 .

3. Zimmermann G , Papke B , Ismail S , Vartak N , Chandra A , Hoffmann M ,

et al. Small molecule inhibition of the KRAS-PDEδ interaction

impairs oncogenic KRAS signalling . Nature 2013 ; 497 : 638 – 42 .

4. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C)

inhibitors allosterically control GTP affi nity and effector interac-

tions. Nature 2013;503:548–51.

5. Singh A , Sweeney MF , Yu M , Burger A , Greninger P , Benes C , et al.

TAK1 inhibition promotes apoptosis in KRAS-dependent colon can-

cers . Cell 2012 ; 148 : 639 – 50 .

6. Adjei AA , Cohen RB , Franklin W , Morris C , Wilson D , Molina JR ,

et al. Phase I pharmacokinetic and pharmacodynamic study of the

oral, small-molecule mitogen-activated protein kinase kinase 1/2

inhibitor AZD6244 (ARRY-142886) in patients with advanced can-

cers . J Clin Oncol 2008 ; 26 : 2139 – 46 .

7. Ganesan P , Janku F , Naing A , Hong DS , Tsimberidou AM , Falchook

GS , et al. Target-based therapeutic matching in early-phase clinical

trials in patients with advanced colorectal cancer and PIK3CA muta-

tions . Mol Cancer Ther 2013 Nov 22 . [Epub ahead of print] .

8. Turke AB , Song Y , Costa C , Cook R , Arteaga CL , Asara JM , et al. MEK

inhibition leads to PI3K/AKT activation by relieving a negative feed-

back on ERBB receptors . Cancer Res 2012 ; 72 : 3228 – 37 .

9. Castellano E , Sheridan C , Thin MZ , Nye E , Spencer-Dene B ,

Diefenbacher ME , et al. Requirement for Interaction of PI3-Kinase

p110alpha with RAS in Lung Tumor Maintenance . Cancer Cell

2013 ; 24 : 617 – 30 .

10. Engelman JA , Chen L , Tan X , Crosby K , Guimaraes AR , Upadhyay R ,

et al. Effective use of PI3K and MEK inhibitors to treat mutant

Kras G12D and PIK3CA H1047R murine lung cancers . Nat Med

2008 ; 14 : 1351 – 6 .

11. Ebi H , Corcoran RB , Singh A , Chen Z , Song Y , Lifshits E , et al.

Receptor tyrosine kinases exert dominant control over PI3K sig-

naling in human KRAS mutant colorectal cancers . J Clin Invest

2011 ; 121 : 4311 – 21 .

12. Corcoran RB , Cheng KA , Hata AN , Faber AC , Ebi H , Coffee EM , et al.

Synthetic lethal interaction of combined BCL-XL and MEK inhibi-

tion promotes tumor regressions in KRAS mutant cancer models .

Cancer Cell 2013 ; 23 : 121 – 8 .

13. Ihle NT , Byers LA , Kim ES , Saintigny P , Lee JJ , Blumenschein GR ,

et al. Effect of KRAS oncogene substitutions on protein behavior:

implications for signaling and clinical outcome . J Natl Cancer Inst

2012 ; 104 : 228 – 39 .

14. Prahallad A , Sun C , Huang S , Di Nicolantonio F , Salazar R , Zecchin

D , et al. Unresponsiveness of colon cancer to BRAF(V600E) inhi-

bition through feedback activation of EGFR . Nature 2012 ; 483 :

100 – 3 .

15. Singh A , Greninger P , Rhodes D , Koopman L , Violette S , Bardeesy

N , et al. A gene expression signature associated with “K-Ras addic-

tion” reveals regulators of EMT and tumor cell survival . Cancer Cell

2009 ; 15 : 489 – 500 .

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