Target Therapy for Hepatocellular Carcinoma: Beyond Receptor Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2022 Apr 23

PMID 35453784

Authors

Hyunjung Park

Hyerin Park

Jiyeon Baek

Hyuk Moon

Simon Weonsang Ro

Affiliations

Soon will be listed here.

Abstract

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. To date, receptor tyrosine kinases (RTKs) are the most favored molecular targets for the treatment of HCC, followed by immune checkpoint regulators such as PD-1, PD-L1, and CTLA-4. With less than desirable clinical outcomes from RTK inhibitors as well as immune checkpoint inhibitors (ICI) so far, novel molecular target therapies have been proposed for HCC. In this review, we will introduce diverse molecular signaling pathways that are aberrantly activated in HCC, focusing on YAP/TAZ, Hedgehog, and Wnt/β-catenin signaling pathways, and discuss potential therapeutic strategies targeting the signaling pathways in HCC.

Citing Articles

MAF1 inhibits hepatocarcinogenesis by fostering an immunostimulatory tumor microenvironment.

Cao D, Wang Y, Sun C, Li H, Ren G, Zhou Y J Immunother Cancer. 2025; 13(1.

PMID: 39800372 PMC: 11749189. DOI: 10.1136/jitc-2024-009656.

Ribosomal proteins in hepatocellular carcinoma: mysterious but promising.

Su Q, Sun H, Mei L, Yan Y, Ji H, Chang L Cell Biosci. 2024; 14(1):133.

PMID: 39487553 PMC: 11529329. DOI: 10.1186/s13578-024-01316-3.

Hepatocellular Carcinoma: Up-regulated Circular RNAs Which Mediate Efficacy in Preclinical Models.

Weidle U, Nopora A Cancer Genomics Proteomics. 2023; 20(6):500-521.

PMID: 37889063 PMC: 10614070. DOI: 10.21873/cgp.20401.

Targeting EGFR/PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma.

Bang J, Jun M, Lee S, Moon H, Ro S Pharmaceutics. 2023; 15(8).

PMID: 37631344 PMC: 10458925. DOI: 10.3390/pharmaceutics15082130.

Infectious Agents Induce Wnt/β-Catenin Pathway Deregulation in Primary Liver Cancers.

Catalano T, Selvaggi F, Esposito D, Cotellese R, Aceto G Microorganisms. 2023; 11(7).

PMID: 37512809 PMC: 10386003. DOI: 10.3390/microorganisms11071632.

References

Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T . AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000; 24(3):245-50. DOI: 10.1038/73448. View

Chen Q, Zhou X, Zhang A, He K . ACTN1 supports tumor growth by inhibiting Hippo signaling in hepatocellular carcinoma. J Exp Clin Cancer Res. 2021; 40(1):23. PMC: 7791991. DOI: 10.1186/s13046-020-01821-6. View

Arzumanyan A, Sambandam V, Clayton M, Choi S, Xie G, Diehl A . Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res. 2012; 72(22):5912-20. PMC: 3521045. DOI: 10.1158/0008-5472.CAN-12-2329. View

Tang E, Wang Y, Liu T, Yan B . Gastrin promotes angiogenesis by activating HIF-1α/β-catenin/VEGF signaling in gastric cancer. Gene. 2019; 704:42-48. DOI: 10.1016/j.gene.2019.04.029. View

Liu Y, Tseng T, Soong R, Peng C, Cheng Y, Huang S . A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment. J Immunother Cancer. 2018; 6(1):144. PMC: 6286542. DOI: 10.1186/s40425-018-0462-3. View

Yi J, Lu L, Yanger K, Wang W, Sohn B, Stanger B . Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ. Hepatology. 2016; 64(5):1757-1772. PMC: 5863546. DOI: 10.1002/hep.28768. View

Le P, Keysar S, Miller B, Eagles J, Chimed T, Reisinger J . Wnt signaling dynamics in head and neck squamous cell cancer tumor-stroma interactions. Mol Carcinog. 2018; 58(3):398-410. PMC: 6460915. DOI: 10.1002/mc.22937. View

Huang A, Yang X, Chung W, Dennison A, Zhou J . Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther. 2020; 5(1):146. PMC: 7419547. DOI: 10.1038/s41392-020-00264-x. View

Han S, Bai E, Jin G, He C, Guo X, Wang L . Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J Immunol Res. 2014; 2014:261365. PMC: 4016924. DOI: 10.1155/2014/261365. View

10.

Yang D, Zhang N, Li M, Hong T, Meng W, Ouyang T . The Hippo Signaling Pathway: The Trader of Tumor Microenvironment. Front Oncol. 2021; 11:772134. PMC: 8632547. DOI: 10.3389/fonc.2021.772134. View

11.

Nhieu J, Renard C, Wei Y, Cherqui D, Zafrani E, Buendia M . Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999; 155(3):703-10. PMC: 1866892. DOI: 10.1016/s0002-9440(10)65168-1. View

12.

Yimlamai D, Christodoulou C, Galli G, Yanger K, Pepe-Mooney B, Gurung B . Hippo pathway activity influences liver cell fate. Cell. 2014; 157(6):1324-1338. PMC: 4136468. DOI: 10.1016/j.cell.2014.03.060. View

13.

Monga S . β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. Gastroenterology. 2015; 148(7):1294-310. PMC: 4494085. DOI: 10.1053/j.gastro.2015.02.056. View

14.

Llovet J, Montal R, Sia D, Finn R . Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018; 15(10):599-616. DOI: 10.1038/s41571-018-0073-4. View

15.

Weinstein I . Cancer. Addiction to oncogenes--the Achilles heal of cancer. Science. 2002; 297(5578):63-4. DOI: 10.1126/science.1073096. View

16.

Briscoe J, Therond P . The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol. 2013; 14(7):416-29. DOI: 10.1038/nrm3598. View

17.

Tao J, Xu E, Zhao Y, Singh S, Li X, Couchy G . Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point-mutant β-catenin. Hepatology. 2016; 64(5):1587-1605. PMC: 5073058. DOI: 10.1002/hep.28601. View

18.

Jeong S, Kim H, Kim M, Lee J, Lee J, Kim J . Hippo-mediated suppression of IRS2/AKT signaling prevents hepatic steatosis and liver cancer. J Clin Invest. 2018; 128(3):1010-1025. PMC: 5824861. DOI: 10.1172/JCI95802. View

19.

Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C . Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018; 17(1):45. PMC: 5817860. DOI: 10.1186/s12943-018-0796-y. View

20.

Pan D . The hippo signaling pathway in development and cancer. Dev Cell. 2010; 19(4):491-505. PMC: 3124840. DOI: 10.1016/j.devcel.2010.09.011. View