Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Author(s): Zhixiong Su, Lei Wang, Xingte Chen, Xiaohong Zhong, Di Wang, Jianchao Wang, Lingdong Shao, Gang Chen* and Junxin Wu*

DOI: 10.2174/1386207325666220204140925

DownloadDownload PDF Flyer Cite As
An Unfolded Protein Response-Related mRNA Signature Predicting the Survival and Therapeutic Effect of Hepatocellular Carcinoma

Page: [2046 - 2058] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background: Tumorigenesis, metastasis, and treatment response of hepatocellular carcinoma (HCC) are regulated by unfolded protein responses (UPR) signaling pathways, including IRE1a, PERK, and ATF6, but little is known about UPR related genes with HCC prognosis and therapeutic indicators.

Objective: We aimed to identify a UPR related prognostic signature (UPRRPS) for HCC and explore the potential effect of the current signature on the existing molecular targeted agents and immune checkpoint inhibitors (ICIs).

Methods: We used The Cancer Genome Atlas (TCGA) database to screen candidate UPR genes (UPRGs), which are expressed differentially between hepatocellular carcinoma and normal liver tissue and associated with prognosis. A gene risk score for overall survival prediction was established using the least absolute shrinkage and selection operator (LASSO) regression analysis, which was validated using data from the International Cancer Genome Consortium (ICGC) database and evaluated by the C-index. Then immune and molecular characteristics stratified by the current UPRRPS were analyzed, and the corresponding drug sensitivity was conducted.

Results: Initially, 42 UPRGs from the TCGA database were screened as differentially expressed genes, which were also associated with HCC prognosis. Using the LASSO regression analysis, nine UPRGs (EXTL3, PPP2R5B, ZBTB17, EIF2S2, EIF2S3, HDGF, SRPRB, EXTL2, and TPP1) were used to develop a UPRRPS to predict the OS of HCC patients in the TCGA set with the Cindex of 0.763. The current UPRRPS was also well-validated in the ICGC set with the C-index of 0.700. Multivariate Cox regression analyses also confirmed that the risk score was an independent risk factor for HCC in both the TCGA and ICGC sets (both P<0.05). Functional analyses showed that low-risk score was associated with increased natural killer cells, T helpers, tumor immune dysfunction and exclusion score, microsatellite instability expression, and more benefit from ICIs; the high-risk score was associated with increased active dendritic cells, Tregs, T-cell exclusion score, and less benefit from ICIs. Gene set enrichment analyses showed that the signaling pathways of VEGF, MAPK, and mTOR were enriched in high UPRRPS, and the drug sensitivities of the corresponding inhibitors were all significantly higher in the high UPRRPS subgroup (all P<0.001).

Conclusion: With the current findings, UPRRPS was a promising biomarker for predicting the prognosis of HCC patients. UPRRPS might also be taken as a potential indicator to guide the management of immune checkpoint inhibitors and molecular targeted agents.

Keywords: Unfolded protein response, hepatocellular carcinoma, drug susceptibility, immune checkpoint inhibitors, molecular targeted agents, tumor immune dysfunction and exclusion.

Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of inci-dence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Singal, A.G.; Lampertico, P.; Nahon, P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J. Hepatol., 2020, 72(2), 250-261.
[http://dx.doi.org/10.1016/j.jhep.2019.08.025] [PMID: 31954490]
[3]
Anwanwan, D.; Singh, S.K.; Singh, S.; Saikam, V.; Singh, R. Challenges in liver cancer and possible treatment approaches. Biochim. Biophys. Acta Rev. Cancer, 2020, 1873(1), 188314.
[http://dx.doi.org/10.1016/j.bbcan.2019.188314] [PMID: 31682895]
[4]
European Association for the Study of the Liver. Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 2018, 69(1), 182-236.
[http://dx.doi.org/10.1016/j.jhep.2018.03.019] [PMID: 29628281]
[5]
Llovet, J.M.; Kelley, R.K.; Villanueva, A.; Singal, A.G.; Pikarsky, E.; Roayaie, S.; Lencioni, R.; Koike, K.; Zucman-Rossi, J.; Finn, R.S. Hepatocellular carcinoma. Nat. Rev. Dis. Primers, 2021, 7(1), 6.
[http://dx.doi.org/10.1038/s41572-020-00240-3] [PMID: 33479224]
[6]
Bruix, J.; Sherman, M. Management of hepatocellular carcinoma: An update. Hepatology, 2011, 53(3), 1020-1022.
[http://dx.doi.org/10.1002/hep.24199] [PMID: 21374666]
[7]
Llovet, J.M.; Zucman-Rossi, J.; Pikarsky, E.; Sangro, B.; Schwartz, M.; Sherman, M.; Gores, G. Hepatocellular carcinoma. Nat. Rev. Dis. Primers, 2016, 2, 16018.
[http://dx.doi.org/10.1038/nrdp.2016.18] [PMID: 27158749]
[8]
Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; de Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; Schwartz, M.; Porta, C.; Zeuzem, S.; Bolondi, L.; Greten, T.F.; Galle, P.R.; Seitz, J.F.; Borbath, I.; Häussinger, D.; Giannaris, T.; Shan, M.; Moscovi-ci, M.; Voliotis, D.; Bruix, J. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359(4), 378-390.
[http://dx.doi.org/10.1056/NEJMoa0708857] [PMID: 18650514]
[9]
Kudo, M.; Finn, R.S.; Qin, S.; Han, K.H.; Ikeda, K.; Piscaglia, F.; Baron, A.; Park, J.W.; Han, G.; Jassem, J.; Blanc, J.F.; Vogel, A.; Komov, D.; Evans, T.R.J.; Lopez, C.; Dutcus, C.; Guo, M.; Saito, K.; Kraljevic, S.; Tamai, T.; Ren, M.; Cheng, A.L. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet, 2018, 391(10126), 1163-1173.
[http://dx.doi.org/10.1016/S0140-6736(18)30207-1] [PMID: 29433850]
[10]
Abou-Alfa, G.K.; Meyer, T.; Cheng, A.L.; El-Khoueiry, A.B.; Rimassa, L.; Ryoo, B.Y.; Cicin, I.; Merle, P.; Chen, Y.; Park, J.W.; Blanc, J.F.; Bolondi, L.; Klümpen, H.J.; Chan, S.L.; Zagonel, V.; Pressiani, T.; Ryu, M.H.; Venook, A.P.; Hessel, C.; Borgman-Hagey, A.E.; Schwab, G.; Kelley, R.K. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med., 2018, 379(1), 54-63.
[http://dx.doi.org/10.1056/NEJMoa1717002] [PMID: 29972759]
[11]
Zhu, A.X.; Kang, Y.K.; Yen, C.J.; Finn, R.S.; Galle, P.R.; Llovet, J.M.; Assenat, E.; Brandi, G.; Pracht, M.; Lim, H.Y.; Rau, K.M.; Motomu-ra, K.; Ohno, I.; Merle, P.; Daniele, B.; Shin, D.B.; Gerken, G.; Borg, C.; Hiriart, J.B.; Okusaka, T.; Morimoto, M.; Hsu, Y.; Abada, P.B.; Kudo, M. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol., 2019, 20(2), 282-296.
[http://dx.doi.org/10.1016/S1470-2045(18)30937-9] [PMID: 30665869]
[12]
Bruix, J.; Qin, S.; Merle, P.; Granito, A.; Huang, Y.H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Breder, V.; Gerolami, R.; Masi, G.; Ross, P.J.; Song, T.; Bronowicki, J.P.; Ollivier-Hourmand, I.; Kudo, M.; Cheng, A.L.; Llovet, J.M.; Finn, R.S.; LeBerre, M.A.; Baumhauer, A.; Meinhardt, G.; Han, G. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 389(10064), 56-66.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[13]
El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T.Y.; Choo, S.P.; Trojan, J.; Welling, T.H.R.; Meyer, T.; Kang, Y.K.; Yeo, W.; Chopra, A.; Anderson, J.; Dela Cruz, C.; Lang, L.; Neely, J.; Tang, H.; Dastani, H.B.; Melero, I. Nivolumab in pa-tients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expan-sion trial. Lancet, 2017, 389(10088), 2492-2502.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[14]
Golfieri, R.; Giampalma, E.; Renzulli, M.; Cioni, R.; Bargellini, I.; Bartolozzi, C.; Breatta, A.D.; Gandini, G.; Nani, R.; Gasparini, D.; Cucchetti, A.; Bolondi, L.; Trevisani, F. Randomised controlled trial of doxorubicin-eluting beads vs. conventional chemoembolisation for hepatocellular carcinoma. Br. J. Cancer, 2014, 111(2), 255-264.
[http://dx.doi.org/10.1038/bjc.2014.199] [PMID: 24937669]
[15]
Urra, H.; Dufey, E.; Avril, T.; Chevet, E.; Hetz, C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer, 2016, 2(5), 252-262.
[http://dx.doi.org/10.1016/j.trecan.2016.03.007] [PMID: 28741511]
[16]
Coleman, O.I.; Lobner, E.M.; Bierwirth, S.; Sorbie, A.; Waldschmitt, N.; Rath, E.; Berger, E.; Lagkouvardos, I.; Clavel, T.; McCoy, K.D.; Weber, A.; Heikenwalder, M.; Janssen, K.P.; Haller, D. Activated ATF6 induces intestinal dysbiosis and innate immune response to pro-mote colorectal tumorigenesis. Gastroenterology, 2018, 155(5), 1539-1552.e12.
[http://dx.doi.org/10.1053/j.gastro.2018.07.028] [PMID: 30063920]
[17]
Wang, L.; Liu, Y.; Du, T.; Yang, H.; Lei, L.; Guo, M.; Ding, H.F.; Zhang, J.; Wang, H.; Chen, X.; Yan, C. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ., 2020, 27(2), 662-675.
[http://dx.doi.org/10.1038/s41418-019-0380-z] [PMID: 31273299]
[18]
Hetz, C.; Zhang, K.; Kaufman, R.J. Mechanisms, regulation and functions of the unfolded protein response. Nat. Rev. Mol. Cell Biol., 2020, 21(8), 421-438.
[http://dx.doi.org/10.1038/s41580-020-0250-z] [PMID: 32457508]
[19]
Wei, J.; Fang, D. Endoplasmic reticulum stress signaling and the pathogenesis of hepatocarcinoma. Int. J. Mol. Sci., 2021, 22(4), 22.
[http://dx.doi.org/10.3390/ijms22041799] [PMID: 33670323]
[20]
Ritchie, M.E.; Phipson, B.; Wu, D.; Hu, Y.; Law, C.W.; Shi, W.; Smyth, G.K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res., 2015, 43(7), e47.
[http://dx.doi.org/10.1093/nar/gkv007] [PMID: 25605792]
[21]
Yu, G.; Wang, L.G.; Han, Y.; He, Q.Y. clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5), 284-287.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[22]
Engebretsen, S.; Bohlin, J. Statistical predictions with glmnet. Clin. Epigenetics, 2019, 11(1), 123.
[http://dx.doi.org/10.1186/s13148-019-0730-1] [PMID: 31443682]
[23]
Mayakonda, A.; Lin, D.C.; Assenov, Y.; Plass, C.; Koeffler, H.P. Maftools: Efficient and comprehensive analysis of somatic variants in cancer. Genome Res., 2018, 28(11), 1747-1756.
[http://dx.doi.org/10.1101/gr.239244.118] [PMID: 30341162]
[24]
Hänzelmann, S.; Castelo, R.; Guinney, J. GSVA: Gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics, 2013, 14, 7.
[http://dx.doi.org/10.1186/1471-2105-14-7] [PMID: 23323831]
[25]
Jiang, P.; Gu, S.; Pan, D.; Fu, J.; Sahu, A.; Hu, X.; Li, Z.; Traugh, N.; Bu, X.; Li, B.; Liu, J.; Freeman, G.J.; Brown, M.A.; Wucherpfennig, K.W.; Liu, X.S. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med., 2018, 24(10), 1550-1558.
[http://dx.doi.org/10.1038/s41591-018-0136-1] [PMID: 30127393]
[26]
Subramanian, A.; Kuehn, H.; Gould, J.; Tamayo, P.; Mesirov, J.P. GSEA-P: A desktop application for gene set enrichment analysis. Bioinformatics, 2007, 23(23), 3251-3253.
[http://dx.doi.org/10.1093/bioinformatics/btm369] [PMID: 17644558]
[27]
Geeleher, P.; Cox, N.; Huang, R.S. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene ex-pression levels. PLoS One, 2014, 9(9), e107468.
[http://dx.doi.org/10.1371/journal.pone.0107468] [PMID: 25229481]
[28]
Polverino, A.; Coxon, A.; Starnes, C.; Diaz, Z.; DeMelfi, T.; Wang, L.; Bready, J.; Estrada, J.; Cattley, R.; Kaufman, S.; Chen, D.; Gan, Y.; Kumar, G.; Meyer, J.; Neervannan, S.; Alva, G.; Talvenheimo, J.; Montestruque, S.; Tasker, A.; Patel, V.; Radinsky, R.; Kendall, R. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit recep-tors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res., 2006, 66(17), 8715-8721.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-4665] [PMID: 16951187]
[29]
Damjanov, N.; Kauffman, R.S.; Spencer-Green, G.T. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: Results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum., 2009, 60(5), 1232-1241.
[http://dx.doi.org/10.1002/art.24485] [PMID: 19404957]
[30]
Chresta, C.M.; Davies, B.R.; Hickson, I.; Harding, T.; Cosulich, S.; Critchlow, S.E.; Vincent, J.P.; Ellston, R.; Jones, D.; Sini, P.; James, D.; Howard, Z.; Dudley, P.; Hughes, G.; Smith, L.; Maguire, S.; Hummersone, M.; Malagu, K.; Menear, K.; Jenkins, R.; Jacobsen, M.; Smith, G.C.; Guichard, S.; Pass, M. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin ki-nase inhibitor with in vitro and in vivo antitumor activity. Cancer Res., 2010, 70(1), 288-298.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1751] [PMID: 20028854]
[31]
Yang, W.; Soares, J.; Greninger, P.; Edelman, E.J.; Lightfoot, H.; Forbes, S.; Bindal, N.; Beare, D.; Smith, J.A.; Thompson, I.R.; Ramaswamy, S.; Futreal, P.A.; Haber, D.A.; Stratton, M.R.; Benes, C.; McDermott, U.; Garnett, M.J. Genomics of Drug Sensitivity in Can-cer (GDSC): A resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res., 2013, 41, D955-D961.
[PMID: 23180760]
[32]
Choi, Y.M.; Lee, S.Y.; Kim, B.J. Naturally occurring hepatitis B virus mutations leading to endoplasmic reticulum stress and their contri-bution to the progression of hepatocellular carcinoma. Int. J. Mol. Sci., 2019, 20(3), 20.
[http://dx.doi.org/10.3390/ijms20030597] [PMID: 30704071]
[33]
Howarth, D.L.; Lindtner, C.; Vacaru, A.M.; Sachidanandam, R.; Tsedensodnom, O.; Vasilkova, T.; Buettner, C.; Sadler, K.C. Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet., 2014, 10(5), e1004335.
[http://dx.doi.org/10.1371/journal.pgen.1004335] [PMID: 24874946]
[34]
Chen, X.; Zhang, F.; Gong, Q.; Cui, A.; Zhuo, S.; Hu, Z.; Han, Y.; Gao, J.; Sun, Y.; Liu, Z.; Yang, Z.; Le, Y.; Gao, X.; Dong, L.Q.; Gao, X.; Li, Y. Hepatic ATF6 increases fatty acid oxidation to attenuate hepatic steatosis in mice through peroxisome proliferator-activated receptor α. Diabetes, 2016, 65(7), 1904-1915.
[http://dx.doi.org/10.2337/db15-1637] [PMID: 27207533]
[35]
Attanasio, S.; Ferriero, R.; Gernoux, G.; De Cegli, R.; Carissimo, A.; Nusco, E.; Campione, S.; Teckman, J.; Mueller, C.; Piccolo, P. Bru-netti-Pierri, N. CHOP and c-JUN up-regulate the mutant Z α1-antitrypsin, exacerbating its aggregation and liver proteotoxicity. J. Biol. Chem., 2020, 295(38), 13213-13223.
[http://dx.doi.org/10.1074/jbc.RA120.014307] [PMID: 32723872]
[36]
Zhao, Y.; Xie, X.; Liao, W.; Zhang, H.; Cao, H.; Fei, R.; Wang, X.; Wei, L.; Shao, Q.; Chen, H. The transcription factor RFX5 is a tran-scriptional activator of the TPP1 gene in hepatocellular carcinoma. Oncol. Rep., 2017, 37(1), 289-296.
[http://dx.doi.org/10.3892/or.2016.5240] [PMID: 27840983]
[37]
Lin, Y.W.; Huang, S.T.; Wu, J.C.; Chu, T.H.; Huang, S.C.; Lee, C.C.; Tai, M.H. Novel HDGF/HIF-1α/VEGF axis in oral cancer impacts disease prognosis. BMC Cancer, 2019, 19(1), 1083.
[http://dx.doi.org/10.1186/s12885-019-6229-5] [PMID: 31711427]
[38]
Ma, Q.; Wu, X.; Wu, J.; Liang, Z.; Liu, T. SERP1 is a novel marker of poor prognosis in pancreatic ductal adenocarcinoma patients via anti-apoptosis and regulating SRPRB/NF-κB axis. Int. J. Oncol., 2017, 51(4), 1104-1114.
[http://dx.doi.org/10.3892/ijo.2017.4111] [PMID: 28902358]
[39]
Zhang, J.; Li, S.; Zhang, L.; Xu, J.; Song, M.; Shao, T.; Huang, Z.; Li, Y. RBP EIF2S2 promotes tumorigenesis and progression by regulating MYC-mediated inhibition via FHIT-related enhancers. Mol. Ther., 2020, 28, 1105-1118.
[40]
Ross, J.; Rashkovan, M.; Fraszczak, J.; Joly-Beauparlant, C.; Vadnais, C.; Winkler, R.; Droit, A.; Kosan, C.; Möröy, T. Deletion of the Miz-1 POZ domain increases efficacy of cytarabine treatment in T- and B-ALL/lymphoma mouse models. Cancer Res., 2019, 79(16), 4184-4195.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3038] [PMID: 31273062]
[41]
Seshacharyulu, P.; Pandey, P.; Datta, K.; Batra, S.K. Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett., 2013, 335(1), 9-18.
[http://dx.doi.org/10.1016/j.canlet.2013.02.036] [PMID: 23454242]
[42]
Loveday, C.; Tatton-Brown, K.; Clarke, M.; Westwood, I.; Renwick, A.; Ramsay, E.; Nemeth, A.; Campbell, J.; Joss, S.; Gardner, M.; Zachariou, A.; Elliott, A.; Ruark, E.; van Montfort, R.; Rahman, N. Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. Hum. Mol. Genet., 2015, 24(17), 4775-4779.
[http://dx.doi.org/10.1093/hmg/ddv182] [PMID: 25972378]
[43]
Wei, W.; He, Y.; Wu, Y.M. Identification of genes associated with SiHa cell sensitivity to paclitaxel by CRISPR-Cas9 knockout screening. Int. J. Clin. Exp. Pathol., 2018, 11(4), 1972-1978.
[PMID: 31938303]
[44]
Sun, Y.; Wu, L.; Zhong, Y.; Zhou, K.; Hou, Y.; Wang, Z.; Zhang, Z.; Xie, J.; Wang, C.; Chen, D.; Huang, Y.; Wei, X.; Shi, Y.; Zhao, Z.; Li, Y.; Guo, Z.; Yu, Q.; Xu, L.; Volpe, G.; Qiu, S.; Zhou, J.; Ward, C.; Sun, H.; Yin, Y.; Xu, X.; Wang, X.; Esteban, M.A.; Yang, H.; Wang, J.; Dean, M.; Zhang, Y.; Liu, S.; Yang, X.; Fan, J. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell, 2021, 184(2), 404-421.e16.
[http://dx.doi.org/10.1016/j.cell.2020.11.041] [PMID: 33357445]
[45]
Schulze, K.; Imbeaud, S.; Letouzé, E.; Alexandrov, L.B.; Calderaro, J.; Rebouissou, S.; Couchy, G.; Meiller, C.; Shinde, J.; Soysouvanh, F.; Calatayud, A.L.; Pinyol, R.; Pelletier, L.; Balabaud, C.; Laurent, A.; Blanc, J.F.; Mazzaferro, V.; Calvo, F.; Villanueva, A.; Nault, J.C.; Bioulac-Sage, P.; Stratton, M.R.; Llovet, J.M.; Zucman-Rossi, J. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet., 2015, 47(5), 505-511.
[http://dx.doi.org/10.1038/ng.3252] [PMID: 25822088]
[46]
Bykov, V.J.N.; Eriksson, S.E.; Bianchi, J.; Wiman, K.G. Targeting mutant p53 for efficient cancer therapy. Nat. Rev. Cancer, 2018, 18(2), 89-102.
[http://dx.doi.org/10.1038/nrc.2017.109] [PMID: 29242642]
[47]
Luo, Y.D.; Fang, L.; Yu, H.Q.; Zhang, J.; Lin, X.T.; Liu, X.Y.; Wu, D.; Li, G.X.; Huang, D.; Zhang, Y.J.; Chen, S.; Jiang, Y.; Shuai, L.; He, Y.; Zhang, L.D.; Bie, P.; Xie, C.M. p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular car-cinoma. J. Hepatol., 2021, 74(1), 96-108.
[http://dx.doi.org/10.1016/j.jhep.2020.07.036] [PMID: 32738450]
[48]
Llovet, J.M. Liver cancer: Time to evolve trial design after everolimus failure. Nat. Rev. Clin. Oncol., 2014, 11(9), 506-507.
[http://dx.doi.org/10.1038/nrclinonc.2014.136] [PMID: 25091613]
[49]
Iñarrairaegui, M.; Melero, I.; Sangro, B. Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin. Cancer Res., 2018, 24(7), 1518-1524.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-0289] [PMID: 29138342]
[50]
Sangro, B.; Gomez-Martin, C.; de la Mata, M.; Iñarrairaegui, M.; Garralda, E.; Barrera, P.; Riezu-Boj, J.I.; Larrea, E.; Alfaro, C.; Sarobe, P.; Lasarte, J.J.; Pérez-Gracia, J.L.; Melero, I.; Prieto, J. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol., 2013, 59(1), 81-88.
[http://dx.doi.org/10.1016/j.jhep.2013.02.022] [PMID: 23466307]
[51]
Saung, M.T.; Pelosof, L.; Casak, S.; Donoghue, M.; Lemery, S.; Yuan, M.; Rodriguez, L.; Schotland, P.; Chuk, M.; Davis, G.; Goldberg, K.B.; Theoret, M.R.; Pazdur, R.; Fashoyin-Aje, L. FDA approval summary: Nivolumab plus ipilimumab for the treatment of patients with hepatocellular carcinoma previously treated with sorafenib. Oncologist, 2021, 26(9), 797-806.
[http://dx.doi.org/10.1002/onco.13819] [PMID: 33973307]
[52]
Alqahtani, A.; Khan, Z.; Alloghbi, A.; Said Ahmed, T.S.; Ashraf, M.; Hammouda, D.M. Hepatocellular carcinoma: Molecular mechanisms and targeted therapies. Medicina (Kaunas), 2019, 55(9), 55.
[http://dx.doi.org/10.3390/medicina55090526] [PMID: 31450841]
[53]
Llovet, J.M.; Montal, R.; Sia, D.; Finn, R.S. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat. Rev. Clin. Oncol., 2018, 15(10), 599-616.
[http://dx.doi.org/10.1038/s41571-018-0073-4] [PMID: 30061739]