Therapeutic targeting of PLK1 in TERT promoter-mutant hepatocellular carcinoma

Abstract

• TERT promoter mutation confers sensitivity to PLK1 inhibitors in HCC.

• The selective growth inhibition of TERT mutant HCC cells induced by PLK1 inhibitor was mediated by Smad3.

• Combined inhibition of PLK1 and Smad3 showed a cooperative anti-tumor effect in TERT mutant HCC cells.

Keywords

hepatocellular carcinoma / PLK1 / Smad3 / TERT promoter mutation

References

[1] SungH, FerlayJ, SiegelRL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.

[2] FinnRS, QinSK, IkedaM, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) plus bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021;39(3).

[3] KudoM, FinnRS, QinS, et al. 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.

[4] RenZG, XuJM, BaiYX, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021;22(8):977-990.

[5] QiuZ, WangC, HuangP, et al. RFX6 facilitates aerobic glycolysis-mediated growth and metastasis of hepatocellular carcinoma through targeting PGAM1. Clin Transl Med. 2023;13(12):e1511.

[6] ZhangH, ZhaiX, LiuY, et al. NOP2-mediated m5C modification of c-Myc in an EIF3A-Dependent manner to reprogram glucose metabolism and promote hepatocellular carcinoma progression. Research (Wash D C). 2023;6:0184.

[7] WangC, CaoY, YangC, Bernards R, QinW. Exploring liver cancer biology through functional genetic screens. Nat Rev Gastroenterol Hepatol. 2021;18(10):690-704.

[8] FujimotoA, FurutaM, TotokiY, et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat Genet. 2016;48(5):500-509.

[9] Cancer Genome Atlas Research Network. Electronic address wbe, Cancer Genome Atlas Research N. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169(7):1327-1341 e1323.

[10] NaultJC, Ningarhari M, RebouissouS, Zucman-RossiJ. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gastroenterol Hepatol. 2019;16(9):544-558.

[11] ShayJW, WrightWE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019;20(5):299-309.

[12] BellRJA, RubeHT, KreigA, et al. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science. 2015;348(6238):1036-1039.

[13] LiY, ZhouQL, SunW, et al. Non-canonical NF-kappaB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation. Nat Cell Biol. 2015;17(10):1327-1338.

[14] HuangFW, HodisE, XuMJ, Kryukov GV, ChinL, GarrawayLA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013;339(6122):957-959.

[15] YanH, Killela PJ, ReitmanZJ, et al. Tert promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Neuro-Oncology. 2014;16.

[16] NaultJC, MalletM, PilatiC, et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun. 2013;4:2218.

[17] GriewankKG, MuraliR, Puig-ButilleJA, et al. TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma. J Natl Cancer Inst. 2014;106(9):dju246.

[18] HiraiM, Kinugasa H, NousoK, et al. Prediction of the prognosis of advanced hepatocellular carcinoma by TERT promoter mutations in circulating tumor DNA. J Gastroenterol Hepatol. 2021;36(4):1118-1125.

[19] Kawai-KitahataF, Asahina Y, TanakaS, et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J Gastroenterol. 2016;51(5):473-486.

[20] LiuR, BishopJ, ZhuG, ZhangT, LadensonPW, Xing M. Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer: genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality. JAMA Oncol. 2017;3(2):202-208.

[21] AgarwalN, Rinaldetti S, CheikhBB, et al. TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer. Proc Natl Acad Sci U S A. 2021;118(38):e2102423118.

[22] ManciniA, Xavier-Magalhaes A, WoodsWS, et al. Disruption of the beta1L isoform of gabp reverses glioblastoma replicative immortality in a TERT promoter mutation-dependent manner. Cancer Cell. 2018;34(3):513-528. e518.

[23] AkincilarSC, Khattar E, BoonPL, UnalB, Fullwood MJ, TergaonkarV. Long-range chromatin interactions drive mutant TERT promoter activation. Cancer Discov. 2016;6(11):1276-1291.

[24] QiuZ, LiH, ZhangZ, et al. A pharmacogenomic landscape in human liver cancers. Cancer Cell. 2019;36(2):179-193. e111.

[25] ValsasinaB, BeriaI, AlliC, et al. NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies. Mol Cancer Ther. 2012;11(4):1006-1016.

[26] CucchiU, Gianellini LM, De PontiA, et al. Phosphorylation of TCTP as a marker for polo-like kinase-1 activity in vivo. Anticancer Res. 2010;30(12):4973-4985.

[27] LenartP, Petronczki M, SteegmaierM, et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1. Curr Biol. 2007;17(4):304-315.

[28] WuKJ, Grandori C, AmackerM, et al. Direct activation of TERT transcription by c-MYC. Nat Genet. 1999;21(2):220-224.

[29] SeyediSA, Nabipoorashrafi SA, HernandezJ, et al. Neutrophil to lymphocyte ratio and spontaneous bacterial peritonitis among cirrhotic patients: a systematic review and meta-analysis. Can J Gastroenterol Hepatol. 2022;2022:8604060.

[30] ShavakhiM, Nourigheimasi S, DiosoE, et al. Prognostic role of neutrophil to lymphocyte ratio in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Can J Gastroenterol Hepatol. 2022;2022:1554079.

[31] SlominskiRM, RamanC, ChenJY, Slominski AT. How cancer hijacks the body's homeostasis through the neuroendocrine system. Trends Neurosci. 2023;46(4):263-275.

[32] MullerM, BirdTG, NaultJC. The landscape of gene mutations in cirrhosis and hepatocellular carcinoma. J Hepatol. 2020;72(5):990-1002.

[33] SchulzeK, Imbeaud S, LetouzeE, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47(5):505-511.

[34] KimRD, SarkerD, MeyerT, et al. First-in-human phase I study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 2019;9(12):1696-1707.

[35] RimassaL, Assenat E, Peck-RadosavljevicM, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19(5):682-693.

[36] LiX, QianX, WangB, et al. Programmable base editing of mutated TERT promoter inhibits brain tumour growth. Nat Cell Biol. 2020;22(3):282-288.

[37] ZhaoG, MaQ, YangH, et al. Base editing of the mutated TERT promoter inhibits liver tumor growth. Hepatology. 2023.

[38] GretenTF, FornerA, KorangyF, et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer. 2010;10:209.

[39] NemunaitisJ, TongAW, NemunaitisM, et al. A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther. 2010;18(2):429-434.

[40] TahtouhR, AzziAS, AlaaeddineN, et al. Telomerase inhibition decreases alpha-fetoprotein expression and secretion by hepatocellular carcinoma cell lines: in vitro and in vivo study. PLoS One. 2015;10(3):e0119512.

[41] AvilionAA, Piatyszek MA, GuptaJ, ShayJW, Bacchetti S, GreiderCW. Human telomerase RNA and telomerase activity in immortal cell lines and tumor tissues. Cancer Res. 1996;56(3):645-650.

[42] FengJ, FunkWD, WangSS, et al. The RNA component of human telomerase. Science. 1995;269(5228):1236-1241.

[43] NakamuraTM, MorinGB, ChapmanKB, et al. Telomerase catalytic subunit homologs from fission yeast and human. Science. 1997;277(5328):955-959.

[44] LiuR, TanJ, ShenX, et al. Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2. Proc Natl Acad Sci U S A. 2021;118(11):e2022779118.

[45] HataA, ChenYG. TGF-beta signaling from receptors to Smads. Cold Spring Harb Perspect Biol. 2016;8(9):a022061.

[46] ShonibareZ, Monavarian M, O'ConnellK, et al. Reciprocal SOX2 regulation by SMAD1-SMAD3 is critical for anoikis resistance and metastasis in cancer. Cell Rep. 2022;40(4):111066.

[47] HuB, TackDC, LiuT, WuZ, UllenbruchMR, PhanSH. Role of Smad3 in the regulation of rat telomerase reverse transcriptase by TGFbeta. Oncogene. 2006;25(7):1030-1041.

[48] LiH, XuD, TohBH, Liu JP. TGF-beta and cancer: is Smad3 a repressor of hTERT gene?Cell Res. 2006;16(2):169-173.

RIGHTS & PERMISSIONS

2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.