Repression of LSD1/KDM1A Activity Improves the Response of Liver Cancer Cells to the Lenvatinib

Overview

Journal Discov Oncol

Publisher Springer

Specialty Oncology

Date 2024 Mar 28

PMID 38538885

Authors

Yi Zong

Zhigang Tao

Siyi Jiang

Minyuan Wang

Weihua Yu

Affiliations

Soon will be listed here.

Abstract

Background/aim: Lenvatinib, a multikinase inhibitor, has become a second-line treatment option for unresectable liver cancer, while its monotherapy response rate is limited. Hence, we aim to investigate whether one of the epigenetic inhibitors will be synthetic lethal with Lenvatinib in liver cancer cells.

Materials And Methods: We performed high-throughput drug screening in combination with Lenvatinib. And we employed CCK-8-based Bliss Synergy Score analysis, colony formation and western blotting to confirm our screening results in both HepG2 and HCCC9810 cells.

Results: We identified that LSD1 inhibitor Pulrodemstat in combination with Lenvatinib dramatically suppressed the PI3K-AKT signaling and induced a more significant activation of Caspase3 compared to Lenvatinib monotherapy.

Conclusion: Pulrodemstat synergized with Lenvatinib based on suppression of PI3K-AKT signaling and activation of apoptotic signaling.

References

Munster P, Thurn K, Thomas S, Raha P, Lacevic M, Miller A . A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer. 2011; 104(12):1828-35. PMC: 3111195. DOI: 10.1038/bjc.2011.156. View

Bitzer M, Horger M, Giannini E, Ganten T, Worns M, Siveke J . Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study. J Hepatol. 2016; 65(2):280-8. DOI: 10.1016/j.jhep.2016.02.043. View

Sheng W, Liu Y, Chakraborty D, Debo B, Shi Y . Simultaneous Inhibition of LSD1 and TGFβ Enables Eradication of Poorly Immunogenic Tumors with Anti-PD-1 Treatment. Cancer Discov. 2021; 11(8):1970-1981. PMC: 8598400. DOI: 10.1158/2159-8290.CD-20-0017. View

Lu Y, Shen H, Huang W, He S, Chen J, Zhang D . Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance. Cell Death Discov. 2021; 7(1):359. PMC: 8602346. DOI: 10.1038/s41420-021-00747-y. 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

Huang M, Lin Y, Wang C, Deng L, Chen M, Assaraf Y . New insights into antiangiogenic therapy resistance in cancer: Mechanisms and therapeutic aspects. Drug Resist Updat. 2022; 64:100849. DOI: 10.1016/j.drup.2022.100849. View

Finn R, Qin S, Ikeda M, Galle P, Ducreux M, Kim T . Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020; 382(20):1894-1905. DOI: 10.1056/NEJMoa1915745. View

Shi G, Huang X, Wu D, Sun H, Liang F, Ji Y . Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study. Signal Transduct Target Ther. 2023; 8(1):106. PMC: 10020443. DOI: 10.1038/s41392-023-01317-7. View

Cabanillas M, Takahashi S . Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. Semin Oncol. 2019; 46(1):57-64. DOI: 10.1053/j.seminoncol.2018.11.004. View

10.

Faletti S, Osti D, Ceccacci E, Richichi C, Costanza B, Nicosia L . LSD1-directed therapy affects glioblastoma tumorigenicity by deregulating the protective ATF4-dependent integrated stress response. Sci Transl Med. 2021; 13(623):eabf7036. DOI: 10.1126/scitranslmed.abf7036. View

11.

Ni M, Li J, Zhao H, Xu F, Cheng J, Yu M . BRD4 inhibition sensitizes cervical cancer to radiotherapy by attenuating DNA repair. Oncogene. 2021; 40(15):2711-2724. DOI: 10.1038/s41388-021-01735-3. View

12.

Hanahan D . Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022; 12(1):31-46. DOI: 10.1158/2159-8290.CD-21-1059. View

13.

Wu B, Pan X, Chen X, Chen M, Shi K, Xu J . Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy. Signal Transduct Target Ther. 2019; 4:11. PMC: 6483994. DOI: 10.1038/s41392-019-0040-2. View

14.

Lim F, Chan A, Yokomori R, Huang X, Theardy M, Yeoh A . Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia. Haematologica. 2022; 108(2):367-381. PMC: 9890034. DOI: 10.3324/haematol.2022.280761. View

15.

Chen C, Wang Y, Wang S, Liu Y, Zhang J, Xu Y . LSD1 sustains estrogen-driven endometrial carcinoma cell proliferation through the PI3K/AKT pathway via di-demethylating H3K9 of cyclin D1. Int J Oncol. 2017; 50(3):942-952. DOI: 10.3892/ijo.2017.3849. View

16.

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

17.

Sang N, Zhong X, Gou K, Liu H, Xu J, Zhou Y . Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B. MedComm (2020). 2023; 4(3):e269. PMC: 10209615. DOI: 10.1002/mco2.269. View

18.

Ju P, Ho Y, Chen P, Lee H, Lai S, Yang S . Kaempferol inhibits the cell migration of human hepatocellular carcinoma cells by suppressing MMP-9 and Akt signaling. Environ Toxicol. 2021; 36(10):1981-1989. DOI: 10.1002/tox.23316. View

19.

Gong Z, Li A, Ding J, Li Q, Zhang L, Li Y . OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis. Adv Sci (Weinh). 2021; 8(15):e2004504. PMC: 8336515. DOI: 10.1002/advs.202004504. View

20.

Donne R, Lujambio A . The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology. 2022; 77(5):1773-1796. PMC: 9941399. DOI: 10.1002/hep.32740. View