Comparative Response of HCC Cells to TKIs: Modified in Vitro Testing and Descriptive Expression Analysis

Overview

Journal J Hepatocell Carcinoma

Date 2022 Jul 18

PMID 35845819

Authors

Paula Sagmeister

Jimmy Daza

Andrea Ofner

Andreas Ziesch

Liangtao Ye

Najib Ben Khaled

Matthias Ebert

Julia Mayerle

Andreas Teufel

Enrico N De Toni

Stefan Munker

Affiliations

Soon will be listed here.

Abstract

Introduction: Although the treatment paradigm for hepatocellular carcinoma (HCC) has recently shifted in favour of checkpoint inhibitor (CPI)-based treatment options, the tyrosine kinase inhibitors (TKI) currently approved for the treatment of HCC are expected to remain the cornerstone of HCC treatment alone or in combination with CPIs. Despite considerable research efforts, no biomarker capable of predicting the response to specific TKIs has been validated. Thus, personalized approaches to HCC may aid in determining optimal treatment lines for 2nd and 3rd lines. To identify new biomarkers, we examined differential sensitivity and investigated potential transcriptomic predictors.

Methods: To this aim, the sensitivity of nine HCC cell lines to sorafenib, lenvatinib, regorafenib, and cabozantinib was evaluated by a prolonged treatment scheme to determine their respective growth rate inhibition concentrations (GR). Subgroups discriminated by GR values underwent differential expression and gene set enrichment analysis (GSEA).

Results: The nine cell lines showed broadly different sensitivities to different TKIs. GR values of sorafenib and regorafenib clustered closer in all cell lines, whereas treatments with lenvatinib and cabozantinib showed diversified GR values. GSEA showed the activation of specific pathways in sensitive vs non-sensitive cell lines. A signature consisting of 14 biomarkers (GAGE12H, GJB6, PTCHD3, PRH1-PRR4, C6orf222, HBB, C17orf99, GOLGA6A, CRYAA, CCL23, RP11-347C12.3, RP11-514O12.4, FAM180B, and TMPRSS4) discriminates the cell lines' response into three distinct treatment profiles: 1) equally sensible to sorafenib, regorafenib and cabozantinib, 2) sensible to lenvatinib, and 3) more sensible to regorafenib than sorafenib.

Conclusion: We observed diverse responses to either of the four TKIs. Subgroup analysis of TKI effectiveness showed distinct transcriptomic profiles and signaling pathways associated with responsiveness. This prompts more extensive studies to explore and validate pharmacogenomic and transcriptomic strategies for a personalized treatment approach, particularly after the failure of CPI treatment.

Citing Articles

Immune-Based Combination Therapies for Advanced Hepatocellular Carcinoma.

Carloni R, Sabbioni S, Rizzo A, Ricci A, Palloni A, Petrarota C J Hepatocell Carcinoma. 2023; 10:1445-1463.

PMID: 37701562 PMC: 10493094. DOI: 10.2147/JHC.S390963.

References

Shaw R, Cantley L . Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441(7092):424-30. DOI: 10.1038/nature04869. View

Hafner M, Niepel M, Chung M, Sorger P . Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nat Methods. 2016; 13(6):521-7. PMC: 4887336. DOI: 10.1038/nmeth.3853. View

Zhang H, Kong Q, Wang J, Jiang Y, Hua H . Complex roles of cAMP-PKA-CREB signaling in cancer. Exp Hematol Oncol. 2020; 9(1):32. PMC: 7684908. DOI: 10.1186/s40164-020-00191-1. View

Alexander J, Bey E, Geddes E, Lecatsas G . Establishment of a continuously growing cell line from primary carcinoma of the liver. S Afr Med J. 1976; 50(54):2124-8. View

Ye L, Mayerle J, Ziesch A, Reiter F, Gerbes A, De Toni E . The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma. Cell Death Discov. 2019; 5:86. PMC: 6450909. DOI: 10.1038/s41420-019-0165-7. View

Vogel A, Saborowski A . Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma. Cancer Treat Rev. 2019; 82:101946. DOI: 10.1016/j.ctrv.2019.101946. View

Dor I, Namba M, Sato J . Establishment and some biological characteristics of human hepatoma cell lines. Gan. 1975; 66(4):385-92. View

Kudo M, Finn R, Qin S, Han K, Ikeda K, Piscaglia F . 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. DOI: 10.1016/S0140-6736(18)30207-1. View

Sebolt-Leopold J, English J . Mechanisms of drug inhibition of signalling molecules. Nature. 2006; 441(7092):457-62. DOI: 10.1038/nature04874. View

10.

Bruix J, Qin S, Merle P, Granito A, Huang Y, Bodoky G . Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2016; 389(10064):56-66. DOI: 10.1016/S0140-6736(16)32453-9. View

11.

Nakabayashi H, Taketa K, Miyano K, Yamane T, Sato J . Growth of human hepatoma cells lines with differentiated functions in chemically defined medium. Cancer Res. 1982; 42(9):3858-63. View

12.

Hafner M, Niepel M, Sorger P . Alternative drug sensitivity metrics improve preclinical cancer pharmacogenomics. Nat Biotechnol. 2017; 35(6):500-502. PMC: 5668135. DOI: 10.1038/nbt.3882. View

13.

Park J, Lee J, Kang M, Park K, Jeon Y, Lee H . Characterization of cell lines established from human hepatocellular carcinoma. Int J Cancer. 1995; 62(3):276-82. DOI: 10.1002/ijc.2910620308. View

14.

Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M . Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008; 14(17):5459-65. DOI: 10.1158/1078-0432.CCR-07-5270. View

15.

Gordan J, Kennedy E, Abou-Alfa G, Beg M, Brower S, Gade T . Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline. J Clin Oncol. 2020; 38(36):4317-4345. DOI: 10.1200/JCO.20.02672. View

16.

Wang S, Yang P . A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma. J Pers Med. 2021; 11(5). PMC: 8145764. DOI: 10.3390/jpm11050332. View

17.

Reiter F, Ben Khaled N, Ye L, Zhang C, Seidensticker M, Op den Winkel M . Advances in Pharmacotherapy of Hepatocellular Carcinoma: A State-of-the-Art Review. Dig Dis. 2021; 40(5):565-580. PMC: 9501734. DOI: 10.1159/000520095. View

18.

Llovet J, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4):378-90. DOI: 10.1056/NEJMoa0708857. View

19.

Larsson P, Engqvist H, Biermann J, Ronnerman E, Forssell-Aronsson E, Kovacs A . Optimization of cell viability assays to improve replicability and reproducibility of cancer drug sensitivity screens. Sci Rep. 2020; 10(1):5798. PMC: 7118156. DOI: 10.1038/s41598-020-62848-5. View

20.

Yakes F, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P . Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011; 10(12):2298-308. DOI: 10.1158/1535-7163.MCT-11-0264. View