www.elsevier.com/locate/jhep

Journal of Hepatology 51 (2009) 638–639

Editorial

Show me your signaling– and I’ll tell you who you are q

Jorn M. Schattenberg, Peter R. Galle*

Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1,

55131 Mainz, Germany

See Article, pages 725–733

Cancer research and therapy have come a long way:the field started out in search of a ‘‘magic bullet” accord-ing to Paul Ehrlich’s theory, and was hoping to identifya target which was pivotal to signaling survival in trans-formed cells. Indeed, certain diseases with monocausalmutations were identified, and targeting of the muta-tional products has helped in the design of treatmentstrategies. In chronic myeloid leukemia (CML), the con-stitutive activation of the tyrosine kinase BCR-ABL ispathognomonic [1], and multiple BCR-ABL kinaseinhibitors (e.g. imatinib mesylate, dasatinib, nilotinib)have been developed and successfully used in the treat-ment of CML offering near-normal life expectancy topatients under continuous therapy. The success of thesecompounds has inspired research in the field of specifickinase inhibitors. Subsequently, it was recognized thatthe developed kinase inhibitors did not exhibit a highdegree of selectivity, but rather caused inhibition of sev-eral kinases [2].

Unfortunately, the success of tyrosine kinase inhibi-tion in haematological malignancies could not be readilytranslated to solid tumors which exhibit a comparativelyhigh degree of genomic alterations of signaling path-ways. Nevertheless, based on the high expression levels

0168-8278/$36.00 � 2009 European Association for the Study of the Liver.

doi:10.1016/j.jhep.2009.05.011

Associate Editor: K. Koikeq M.J.S. declared that he does not have anything to disclose

regarding funding or conflict of interest with respect to this manu-script. P.R.G. receives lecture and consultant fees from Bayer AG,Leverkusen, Germany.

* Corresponding author. Tel.: +49 6131 177275/6; fax: +49 6131175595.

E-mail address: galle@uni-mainz.de (P.R. Galle).Abbreviations: CML, chronic myeloid leukemia; HCC, hepatocellu-

lar carcinoma.

of EGFR and HER-2 in solid tumors, EGFR inhibitorssuch as gefitinib and erlotinib were developed. Theirimplementation in various malignancies resulted in clin-ically meaningful, although moderate improvement ofoverall survival for different tumor entities and theywere first introduced for non-small-cell lung cancer [3].Other tumor entities followed and currently eight kinaseinhibitors are FDA-approved. The indication for useincludes hepatocellular carcinoma (HCC), where amajor breakthrough was achieved in the SHARP trialin 2008 which demonstrated improved survival inpatients with advanced HCC receiving sorafenib [4].Sorafenib was shown to inhibit roughly 15 kinases atnanomolar potency [2] supporting the concept that a‘‘dirty inhibitory effect” on multiple kinases rather thanon a single signaling molecule will lead to recognizableresponses in the treatment of solid organ tumors includ-ing HCC [4]. As a consequence, the precise mode ofaction of sorafenib needs further clarification.

The work presented by Newell and colleagues in thecurrent issue of the Journal of Hepatology [5] examinesthe antineoplastic potential of combining sorafenib withrapamycin, an inhibitor of the mTOR pathway, inexperimental hepatocarcinogenesis. In agreement withan earlier study by Wang et al. [6], the combination ofthe two compounds lead to an additive effect withrespect to reduced cell proliferation, increased cancercell apoptosis and increased tumor necrosis in a xeno-graft model of HCC. The combination of these twoagents is appealing since two independent signalingpathways which have been both implicated in the path-ophysiology of HCC are targeted [7]. While sorafenibinhibits the Ras/Raf/MEK/Erk pathway [8], rapamycininhibits activation of the mTOR complex downstream

Published by Elsevier B.V. All rights reserved.

J.M. Schattenberg, P.R. Galle / Journal of Hepatology 51 (2009) 638–639 639

of the phosphoinositide 3-kinase (PI3K) and Akt. Bothpathways promote proliferation in HCC [9]. Additionalevidence supporting the rationale of simultaneous inhi-bition of more than one signaling pathway comes fromstudies showing a compensatory overactivation of oneparallel growth promoting pathway following signalinhibition of another. In this sense mTOR inhibitioncan result in compensatory activation of the Ras signal-ing pathway leading to cancer cell resistance [10] andthus, additional Ras inhibition potentially counteractssuch a compensatory mechanism.

Apart from the biological response in the xenograftmodel, the authors found changes in methylation pat-terns of oncogens of the Ras pathway in advancedtumor stages. It is difficult to assess the biological mean-ing of such observations and it is likely that manychanges that are seen in dedifferentiated tumor tissueoccur without significantly contributing to tumor biol-ogy and thus the relevance of those in vitro findings inpredicting potential targets or markers that can be use-ful in clinical trials is questionable.

In order to separate signal from noise, to identify pre-dominant signaling pathways in solid tumors, definingtumor biology, the concept of oncogenic addiction hasbeen developed [11]. This concept was derived fromobservations revealing tumorous tissue to be dependenton only one or a few genes for cell survival and main-taining the malignant phenotype despite a high degreeof genetic and epigenetic abnormalities [11]. Identifica-tion of these pivotal pathways which are crucial totumor cell survival will advance the success in the treat-ment of HCC rapidly. In addition to the above men-tioned pathways, important targets to be assessed forcombination therapy include the Wnt/b-catenin path-way, cell cycle regulators (CDK), angiogenic factors(VEGFR and PDGFR) and proteases such as MMP-14, MMP-9 or topoisomerase [12]. As long as tumordefining signaling pathways can not be defined preciselyenough to develop highly selective inhibitors of down-stream targets aimed to inhibit the oncogenes, whichare crucial to tumor cell growth, low selectivity as seenwith sorafenib will help to achieve an anti-tumor effectsdespite the lack of knowledge of the exact mechanisms.Moreover, the combined inhibition through unspecifici-ty or the addition of a second pathway inhibitor mighthelp to overcome resistance attributable to activationof multiple cell growth pathways. The challenge offuture research in this field will be to engineer reliablesystems that predict targets which will lead to inhibitionof the pathway the tumor ‘‘is addicted to”. In the agepast the ‘‘Human Genome Project” tumor biology willhave to develop treatment strategies detached from a

deterministic, genetic view and produce ‘‘pathway fin-gerprints” of a tumor which can predict the individual-ized response towards inhibition of kinases orcombinations thereof. These concepts will rely on sys-tem biology which will help to predict the response oftumors to pathway inhibition depending on the predom-inant tumor biology and to define future targets oftherapy.

However the biggest challenge will remain, regardlesshow good the rationale for testing drugs has been elab-orated in vitro: clinical trials still have to be used in theend to define the benefit for the patient and here we haveseen many surprises of success and failure previously notpredicted on theoretical grounds.

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