Ras pathway activation in hepatocellular carcinoma and anti-tumoral effect of combined sorafenib and rapamycin in vivo

JOURNAL OF HEPATOLOGY

卷:51

Article

Newell, Pippa^{9,10,11,12,13}  Toffanin, Sara^{8,9,10,11,12,13}  Villanueva, Augusto^6,7  Chiang, Derek Y.^3,4,5  Minguez, Beatriz^{9,10,11,12,13}  Cabellos, Laia^{9,10,11,12,13}  Savic, Radoslav^{9,10,11,12,13}  Hoshida, Yujin^2,3  Lim, Kiat Hon^{9,10,11,12,13}  Melgar-Lesmes, Pedro^{9,10,11,12,13}  Yea, Steven^{9,10,11,12,13}  Peix, Judit^6,7  Deniz, Kemal^{9,10,11,12,13}  Fiel, M. Isabel^{9,10,11,12,13}  Thung, Swan^{9,10,11,12,13}  Alsinet, Clara^6,7  Tovar, Victoria^6,7  Mazzaferro, Vincenzo⁸  Bruix, Jordi^6,7  Roayaie, Sasan^{9,10,11,12,13}  Schwartz, Myron^{9,10,11,12,13}  Friedman, Scott L.^{9,10,11,12,13}  Llovet, Josep M.^{1,6,7,9,10,11,12,13} 

[1] Inst Catalana Recerca & Estudis Avancats, Barcelona, Catalonia, Spain

[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[3] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA USA

[4] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[6] Hosp Clin Barcelona, CIBERehd, IDIBAPS, BCLC Grp,HCC Translat Res Lab,Liver Unit, Barcelona, Catalonia, Spain

[7] Hosp Clin Barcelona, CIBERehd, Dept Pathol, IDIBAPS,BCLC Grp, Barcelona, Catalonia, Spain

[8] IRCSS Fdn, Natl Canc Inst, Gastrointestinal Surg & Liver Transplantat Unit, Milan, Italy

[9] Mt Sinai Sch Med, Mt Sinai Liver Canc Program, Div Liver Dis & Hematooncol, New York, NY 10029 USA

[10] Mt Sinai Sch Med, Dept Med, Mt Sinai Liver Canc Program, New York, NY 10029 USA

[11] Mt Sinai Sch Med, Div Surg Oncol, Mt Sinai Liver Canc Program, New York, NY 10029 USA

[12] Mt Sinai Sch Med, Dept Surg, Mt Sinai Liver Canc Program, New York, NY 10029 USA

[13] Mt Sinai Sch Med, Dept Pathol, Mt Sinai Liver Canc Program, New York, NY 10029 USA

关键词: Liver cancer;    HCV;    Signaling pathway;    Molecular therapies;    Ras;    mTOR;   

DOI  :  10.1016/j.jhep.2009.03.028

来源: Elsevier

【 摘 要 】

Background/Aims: The success of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC) has focused interest on the role of Ras signaling in this malignancy. We investigated the molecular alterations of the Ras pathway in HCC and the antineoplastic effects of sorafenib in combination with rapamycin, an inhibitor of mTOR pathway, in experimental models. Methods: Gene expression (qRT-PCR, oligonucleotide microarray), DNA copy number changes (SNP-array), methylation of tumor suppressor genes (methylation specific PCR) and protein activation (immunohistochemistry) were analysed in 351 samples. Anti-tumoral effects of combined therapy, targeting the Ras and mTOR pathways were evaluated in cell lines and HCC xenografts. Results: Different mechanisms accounted for Ras pathway activation in HCC. H-ran was up-regulated during different steps of hepatocarcinogenesis. B-raf was overexpressed in advanced tumors and its expression was associated with genomic amplification. Partial methylation of RASSFIA and NOREIA was detected in 89%, and 44%, of tumors respectively, and complete methylation was found in 11 and 4%, of HCCs. Activation of the pathway (PERK immunostaining) was identified in 10.3'% of HCC. Blockade of Ras and mTOR pathways with sorafenib and rapamycin reduced cell proliferation and induced apoptosis in cell lines. In vivo, the combination of both compounds enhanced tumor necrosis and ulceration when compared with sorafenib alone. Conclusions: Ras activation results from several molecular alterations, such as methylation of tumor suppressors and amplification of oncogenes (B-raf). Sorafenib blocks signaling and synergizes with rapamycin in vivo, preventing tumor progression. These data provide the rationale for testing this combination in clinical studies. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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