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

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    Show me your signaling and

    Jorn M. Schattenberg

    of th

    inz, G


    degree of selectivity, but rather caused inhibition of sev- ing HCC [4]. As a consequence, the precise mode of

    ophysiology of HCC are targeted [7]. While sorafenibinhibits the Ras/Raf/MEK/Erk pathway [8], rapamycininhibits activation of the mTOR complex downstream

    iver. Published by Elsevier B.V. All rights reserved.

    175595.E-mail address: (P.R. Galle).Abbreviations: CML, chronic myeloid leukemia; HCC, hepatocellu-

    lar carcinoma.

    Journal of Hepatology 51 (0168-8278/$36.00 2009 European Association for the Study of the Lhigh degree of genomic alterations of signaling path-ways. Nevertheless, based on the high expression levels

    rapamycin, 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 eect 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-

    Associate Editor: K. Koikeq M.J.S. declared that he does not have anything to discloseregarding funding or conict 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 6131translated to solid tumors which exhibit a comparativelyUnfortunately, the success of tyrosine kinase inhibi-tion in haematological malignancies could not be readily

    The work presented by Newell and colleagues in thecurrent issue of the Journal of Hepatology [5] examinesthe antineoplastic potential of combining sorafenib witheral kinases [2]. action of sorafenib needs further clarication.Department of Internal Medicine, University Medical Center

    55131 Ma

    See Article,

    Cancer research and therapy have come a long way:the eld started out in search of a magic bullet accord-ing to Paul Ehrlichs theory, and was hoping to identifya target which was pivotal to signaling survival in trans-formed cells. Indeed, certain diseases with monocausalmutations were identied, 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 oering near-normal life expectancy topatients under continuous therapy. The success of thesecompounds has inspired research in the eld of specickinase inhibitors. Subsequently, it was recognized thatthe developed kinase inhibitors did not exhibit a highdoi:10.1016/j.jhep.2009.05.011ial

    Ill tell you who you areq

    , Peter R. Galle*

    e Johannes Gutenberg University Mainz, Langenbeckstr. 1,


    es 725733

    of EGFR and HER-2 in solid tumors, EGFR inhibitorssuch as getinib and erlotinib were developed. Theirimplementation in various malignancies resulted in clin-ically meaningful, although moderate improvement ofoverall survival for dierent tumor entities and theywere rst 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 adirty inhibitory eect on multiple kinases rather thanon a single signaling molecule will lead to recognizableresponses in the treatment of solid organ tumors includ-

    2009) 638639

  • of the phosphoinositide 3-kinase (PI3K) and Akt. Bothpathways promote proliferation in HCC [9]. Additionalevidence supporting the rationale of simultaneous inhi-

    deterministic, genetic view and produce pathway n-gerprints of a tumor which can predict the individual-

    inhibitor that targets both Raf and VEGF and PDGF

    J.M. Schattenberg, P.R. Galle / Journal of Hepatology 51 (2009) 638639 639bition 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 dicult to assess the biological mean-ing of such observations and it is likely that manychanges that are seen in dedierentiated tumor tissueoccur without signicantly contributing to tumor biol-ogy and thus the relevance of those in vitro ndings 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, deningtumor 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]. Identica-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 tumordening signaling pathways can not be dened 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 eectsdespite the lack of knowledge of the exact mechanisms.Moreover, the combined inhibition through unspecici-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 eld 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 areceptor tyrosine kinase signaling. Mol Cancer Ther 2008;7:31293140.

    [9] Pang RW, Poon RT. From molecular biology to targetedtherapies for hepatocellular carcinoma: the future is now. Oncol-ogy 2007;72:3044.

    [10] Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L,Alimonti A, et al. Inhibition of mTORC1 leads to MAPKpathway activation through a PI3K-dependent feedback loop inhuman cancer. J Clin Invest 2008;118:30653074.

    [11] Weinstein IB, Joe AK. Mechanisms of disease: oncogene addic-tion a rationale for molecular targeting in cancer therapy. NatClin Pract Oncol 2006;3:448457.

    [12] Llovet JM, Bruix J. Molecular targeted therapies in hepatocellularcarcinoma. Hepatology 2008;48:13121327.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 dene 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 dene the benet for the patient and here we haveseen many surprises of success and failure previously notpredicted on theoretical grounds.


    [1] Daley GQ, Van Etten RA, Baltimore D. Induction of chronicmyelogenous leukemia in mice by the P210bcr/abl gene of thePhiladelphia chromosome. Science 1990;247:824830.

    [2] Chaparro M, Gonzalez ML, Trapero-Marugan M, Medina J,Moreno-Otero R. Review article: pharmacological therapy forhepatocellular carcinoma with sorafenib and other oral agents.Aliment Pharmacol Ther 2008;28:12691277.

    [3] Ghoreschi K, Laurence A, OShea JJ. Selectivity and therapeuticinhibition of kinases: to be or not to be? Nat Immunol2009;10:356360.

    [4] Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF,et al. Sorafenib in advanced hepatocellular carcinoma. N Engl JMed 2008;359:378390.

    [5] Newell P, Toanin S, Villanueva A, Chiang DY, Minguez B,Cabellos L, et al. Ras pathway activation in hepatocellular carci-noma and anti-tumoral eect of combined sorafenib and rapa-mycin in vivo. J Hepatol 2009;51:725733.

    [6] Wang Z, Zhou J, Fan J, Qiu SJ, Yu Y, Huang XW, et al. Eect ofrapamycin alone and in combination with sorafenib in anorthotopic model of human hepatocellular carcinoma. ClinCancer Res 2008;14:51245130.

    [7] Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C,et al. Pivotal role of mTOR signaling in hepatocellular carcinoma.Gastroenterology 2008;135:19721983.

    [8] Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM,Lynch M. Preclinical overview of sorafenib, a multikinase

    Show me your signaling and Ill tell you who you areReferences


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