6533b855fe1ef96bd12aff9a

RESEARCH PRODUCT

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

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See Article, pages 725–733Cancer 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 levelsof 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