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Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma

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Abstract

Purpose

Preclinical studies show that sorafenib, a multitarget kinase inhibitor, displays anti-proliferative, anti-angiogenic, and pro-apoptotic properties in hepatocellular carcinoma (HCC). However, the determinants of sorafenib sensitivity in vivo remain largely unknown.

Methods

We assessed the expression of Mcl-1, activated/phosphorylated extracellular signal-regulated kinase (pERK) 1/2, and activated/phosphorylated AKT (pAKT) in pretreatment tumor specimens from 44 patients with advanced HCC who received sorafenib. Furthermore, we assessed MYC and MET gene copy numbers (GCN) by fluorescence in situ hybridization.

Results

Poorer overall survival (OS) times were correlated with pERK expression [hazard ratio (HR) 1.013; 95 % CI 1.003–1.035] and Mcl-1 expression (HR 1.016; 95 % CI 1.002–1.030) in pretreatment tumor samples. Expression levels of pERK and Mcl-1, however, were not correlated with time to tumor progression (TTP). Increased pERK expression was positively associated with higher Cancer of Liver Italian Program scores (P = 0.012) and was prognostic in patients with scores 2–6 but not in those with scores 0–1. pERK expression was significantly less frequent in specimens sourced from previous surgical procedures compared to biopsy samples (9.6 vs. 92.3 %, respectively; P < 0.0001). Analysis of pAKT expression, MET and MYC GCN, did not indicate any prognostic nor predictive values for these biomarkers in terms of survival.

Conclusions

Expression levels of Mcl-1 and pERK are associated with reduced OS in HCC patients treated with sorafenib and might be useful markers for risk stratification. However, in contrast to previous findings, pERK expression levels, as well as other biomarkers tested, did not affect TTP.

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References

  • Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:4293–4300

    Article  PubMed  CAS  Google Scholar 

  • Baker AF, Dragovich T, Ihle NT, Williams R, Fenoglio-Preiser C, Powis G (2005) Stability of phosphoprotein as a biological marker of tumor signaling. Clin Cancer Res 11:4338–4340

    Article  PubMed  CAS  Google Scholar 

  • Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, Del Grammastro M, Sciarrotta MG, Buttitta F, Incarbone M, Toschi L, Finocchiaro G, Destro A, Terracciano L, Roncalli M, Alloisio M, Santoro A, Varella-Garcia M (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27:1667–1674

    Article  PubMed  Google Scholar 

  • Chan KL, Guan XY, Ng IO (2004) High-throughput tissue microarray analysis of c-myc activation in chronic liver diseases and hepatocellular carcinoma. Hum Pathol 35:1324–1331

    Article  PubMed  CAS  Google Scholar 

  • Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8:705–711

    Article  PubMed  CAS  Google Scholar 

  • Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34

    Article  PubMed  CAS  Google Scholar 

  • Ding Q, Huo L, Yang JY, Xia W, Wei Y, Liao Y, Chang CJ, Yang Y, Lai CC, Lee DF, Yen CJ, Chen YJ, Hsu JM, Kuo HP, Lin CY, Tsai FJ, Li LY, Tsai CH, Hung MC (2008) Down-regulation of myeloid cell leukemia-1 through inhibiting Erk/Pin 1 pathway by sorafenib facilitates chemosensitization in breast cancer. Cancer Res 68:6109–6117

    Article  PubMed  CAS  Google Scholar 

  • Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW (2004) MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene 23:5301–5315

    Article  PubMed  CAS  Google Scholar 

  • Farinati F, Marino D, De Giorgio M, Baldan A, Cantarini M, Cursaro C, Rapaccini G, Del Poggio P, Di Nolfo MA, Benvegnù L, Zoli M, Borzio F, Bernardi M, Trevisani F (2006) Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol 101:524–532

    Article  PubMed  CAS  Google Scholar 

  • Fleischer B, Schulze-Bergkamen H, Schuchmann M, Weber A, Biesterfeld S, Müller M, Krammer PH, Galle PR (2006) Mcl-1 is an anti-apoptotic factor for human hepatocellular carcinoma. Int J Oncol 28:25–32

    PubMed  CAS  Google Scholar 

  • Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, Newell P, Ikeda K, Hashimoto M, Watanabe G, Gabriel S, Friedman SL, Kumada H, Llovet JM, Golub TR (2009) Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 69:7385–7392

    Article  PubMed  CAS  Google Scholar 

  • Jiang SX, Yamashita K, Yamamoto M, Piao CJ, Umezawa A, Saegusa M, Yoshida T, Katagiri M, Masuda N, Hayakawa K, Okayasu I (2008) EGFR genetic heterogeneity of nonsmall cell lung cancers contributing to acquired gefitinib resistance. Int J Cancer 123:2480–2486

    Article  PubMed  CAS  Google Scholar 

  • Jilaveanu L, Zito C, Lee SJ, Nathanson KL, Camp RL, Rimm DL, Flaherty KT, Kluger HM (2009) Expression of sorafenib targets in melanoma patients treated with carboplatin, paclitaxel and sorafenib. Clin Cancer Res 15:1076–1085

    Article  PubMed  CAS  Google Scholar 

  • Kaposi-Novak P, Lee JS, Gòmez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 116:1582–1595

    Article  PubMed  CAS  Google Scholar 

  • Ke AW, Shi GM, Zhou J, Wu FZ, Ding ZB, Hu MY, Xu Y, Song ZJ, Wang ZJ, Wu JC, Bai DS, Li JC, Liu KD, Fan J (2009) Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology 49:491–503

    Article  PubMed  CAS  Google Scholar 

  • Kim TM, Yim SH, Shin SH, Xu HD, Jung YC, Park CK, Choi JY, Park WS, Kwon MS, Fiegler H, Carter NP, Rhyu MG, Chung YJ (2008) Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q. Int J Cancer 123:2808–2815

    Article  PubMed  CAS  Google Scholar 

  • Kondo S, Ojima H, Tsuda H, Hashimoto J, Morizane C, Ikeda M, Ueno H, Tamura K, Shimada K, Kanai Y, Okusaka T (2012) Clinical impact of c-Met expression and its gene amplification in hepatocellular carcinoma. Int J Clin Oncol (Epub Jan 5)

  • Krajewski S, Bodrug S, Krajewska M, Shabaik A, Gascoyne R, Berean K, Reed JC (1995) Immunohistochemical analysis of Mcl-1 protein in human tissues. Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo. Am J Pathol 146:1309–1319

    PubMed  CAS  Google Scholar 

  • Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C (2006) Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66:11851–11858

    Article  PubMed  CAS  Google Scholar 

  • Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390

    Article  Google Scholar 

  • Nomura F, Ohnishi K, Tanabe Y (1989) Clinical features and prognosis of hepatocellular carcinoma with reference to serum alpha-fetoprotein levels. Analysis of 606 patients. Cancer 64:1700–1707

    Article  PubMed  CAS  Google Scholar 

  • Oliner KS, Tang R, Anderson A, Lan Y, Iveson T, Donehower RC, Jiang Y, Dubey S, Loh E (2012) Evaluation of MET pathway biomarkers in a phase II study of rilotumumab (R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin, and capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric (G) or esophagogastric junction (EGJ) cancer. J Clin Oncol 30(Suppl):Abstract 4005

    Google Scholar 

  • Perciavalle RM, Opferman JT (2013) Delving deeper: MCL-1’s contributions to normal and cancer biology. Trends Cell Biol 23:22–29

    Article  PubMed  CAS  Google Scholar 

  • Personeni N, Bozzarelli S, Pressiani T, Rimassa L, Tronconi MC, Sclafani F, Carnaghi C, Pedicini V, Giordano L, Santoro A (2012) Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma. J Hepatol 57:101–107

    Article  PubMed  CAS  Google Scholar 

  • Pressiani T, Boni C, Rimassa L, Labianca R, Fagiuoli S, Salvagni S, Ferrari D, Cortesi E, Porta C, Mucciarini C, Latini L, Carnaghi C, Banzi M, Fanello S, De Giorgio M, Lutman FR, Torzilli G, Tommasini MA, Ceriani R, Covini G, Tronconi MC, Giordano L, Locopo N, Naimo S, Santoro A (2013) Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis. Ann Oncol 24:406–411

    Article  PubMed  CAS  Google Scholar 

  • Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S, Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z, Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y, Porta C (2013) Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 14:55–63

    Article  PubMed  CAS  Google Scholar 

  • Schlaeger C, Longerich T, Schiller C, Bewerunge P, Mehrabi A, Toedt G, Kleeff J, Ehemann V, Eils R, Lichter P, Schirmacher P, Radlwimmer B (2008) Etiology-dependent molecular mechanisms in human hepatocarcinogenesis. Hepatology 47:511–520

    Article  PubMed  CAS  Google Scholar 

  • Schmitz KJ, Wohlschlaeger J, Lang H, Sotiropoulos GC, Malago M, Steveling K, Reis H, Cicinnati VR, Schmid KW, Baba HA (2008) Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 48:83–90

    Article  PubMed  CAS  Google Scholar 

  • Sieghart W, Losert D, Strommer S, Cejka D, Schmid K, Rasoul-Rockenschaub S, Bodingbauer M, Crevenna R, Monia BP, Peck-Radosavljevic M, Wacheck V (2006) Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy. J Hepatol 44:151–157

    Article  PubMed  CAS  Google Scholar 

  • Stuart KE, Anand AJ, Jenkins RL (1996) Hepatocellular carcinoma in the United States. Prognostic features, treatment outcome, and survival. Cancer 77:2217–2222

    Article  PubMed  CAS  Google Scholar 

  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  • Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E (1997) Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinoma. Hepatology 25:862–866

    Article  PubMed  CAS  Google Scholar 

  • Verslype C, Cohn AL, Kelley RK, Yang TS, Su WC, Ramies DA, Lee Y, Shen X, Van Cutsem E (2012) Activity of cabozantinib (XL184) in hepatocellular carcinoma: results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 30(Suppl):Abstract 4007

    Google Scholar 

  • Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, Zhuang SM (2010) Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 51:836–845

    PubMed  CAS  Google Scholar 

  • Yu C, Bruzek LM, Meng XW, Gores GJ, Carter CA, Kaufmann SH, Adjei AA (2005) The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 24:6861–6869

    Article  PubMed  CAS  Google Scholar 

  • Zhang Z, Zhou X, Shen H, Wang D, Wang Y (2009) Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitro study. BMC Med 7:41

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank research staff and technicians from the Department of Pathology at Humanitas Cancer Center, Istituto Clinico Humanitas IRCCS, for their supportive work in immunohistochemistry testing and logistics.

Conflict of interest

Armando Santoro has participated in advisory activities for Bayer HealthCare Pharmaceuticals. No potential conflicts of interest were disclosed by the other authors.

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Authors and Affiliations

  1. Department of Oncology-Hematology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano (Mi), Italy

    Nicola Personeni, Lorenza Rimassa, Tiziana Pressiani, Claudia Ligorio, Maria Chiara Tronconi, Silvia Bozzarelli, Carlo Carnaghi & Armando Santoro

  2. Department of Pathology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano (Mi), Italy

    Annarita Destro, Luca Di Tommaso & Massimo Roncalli

  3. Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano (Mi), Italy

    Laura Giordano

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  1. Nicola Personeni
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  2. Lorenza Rimassa
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  12. Armando Santoro
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Correspondence to Nicola Personeni.

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Personeni, N., Rimassa, L., Pressiani, T. et al. Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 139, 1179–1187 (2013). https://doi.org/10.1007/s00432-013-1429-x

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  • DOI: https://doi.org/10.1007/s00432-013-1429-x

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