Email this article SHR6390 Combined with Cabozantinib Inhibits Tumor Progression in the Hepatocellular Carcinoma Mouse Model
- Authors: Liu C.1, Han P.2, Zhang Y.1, Wang Y.3, Nie J.1, Shan D.1, Zhou M.1, Lin B.1, Shi J.1, Zheng T.1
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Affiliations:
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
- Department of General Surgery, the First Affiliated Hospital of Harbin Medical University
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital
- Issue: Vol 24, No 5 (2024)
- Pages: 453-464
- Section: Life Sciences
- URL: https://gynecology.orscience.ru/1566-5232/article/view/644082
- DOI: https://doi.org/10.2174/1566523222666220825110147
- ID: 644082
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Abstract
Background:A novel CDK4/6 inhibitor SHR6390 has shown significant anti-tumor effects. However, its role in hepatocellular carcinoma (HCC) remains unknown.
Objective:To explore the inhibitory effect of combination treatment with SHR6390 and cabozantinib in HCC, and its antitumor mechanism, so as to provide a more effective therapeutic strategy for HCC patients.
Methods:We investigated SHR6390, monotherapy or combined with cabozantinib, by CCK8, wound healing, transwell, western blotting, immunohistochemistry and mouse model of a subcutaneous tumor.
Results:Our results show that SHR6390 exhibited potent anti-proliferative activity against HCC in a dose-dependent manner. SHR6390 combined with cabozantinib exhibited more potent inhibition of cell viability, migration and invasion. In terms of potential mechanisms, we found that cabozantinib could lead to phosphorylation of Rb, which was reduced in SHR6390 and combined groups. SHR6390 monotherapy inhibited the growth of subcutaneous HCC tumors, besides, the combination treatment with SHR6390 and cabozantinib exerted synergistic anti-tumor activity in vivo.
Conclusion:SHR6390 is effective against HCC, monotherapy or combined with cabozantinib.
Keywords
About the authors
Caiqi Liu
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Peng Han
Department of General Surgery, the First Affiliated Hospital of Harbin Medical University
Author for correspondence.
Email: info@benthamscience.net
Yanqiao Zhang
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Yan Wang
Department of Colorectal Surgery, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Jianhua Nie
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Dan Shan
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Meng Zhou
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Binlin Lin
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Jiaqi Shi
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Email: info@benthamscience.net
Tongsen Zheng
Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital
Author for correspondence.
Email: info@benthamscience.net
References
- Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424. doi: 10.3322/caac.21492 PMID: 30207593
- Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10(1): 25-34. doi: 10.1016/S1470-2045(08)70285-7 PMID: 19095497
- Bruix J, Qin S, Merle P, et al. 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. doi: 10.1016/S0140-6736(16)32453-9 PMID: 27932229
- Bhoori S, Mazzaferro V. Combined immunotherapy and VEGF-antagonist in hepatocellular carcinoma: A step forward. Lancet Oncol 2020; 21(6): 740-1. doi: 10.1016/S1470-2045(20)30211-4 PMID: 32502436
- Shen S, Dean DC, Yu Z, Duan Z. Role of cyclin-dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway. Hepatol Res 2019; 49(10): 1097-108. doi: 10.1111/hepr.13353 PMID: 31009153
- Gao X, Leone GW, Wang H. Cyclin D-CDK4/6 functions in cancer. Adv Cancer Res 2020; 148: 147-69. doi: 10.1016/bs.acr.2020.02.002 PMID: 32723562
- Goel S, DeCristo MJ, McAllister SS, Zhao JJ. CDK4/6 inhibition in cancer: Beyond cell cycle arrest. Trends Cell Biol 2018; 28(11): 911-25. doi: 10.1016/j.tcb.2018.07.002 PMID: 30061045
- Yuan K, Wang X, Dong H, Min W, Hao H, Yang P. Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs. Acta Pharm Sin B 2021; 11(1): 30-54. doi: 10.1016/j.apsb.2020.05.001 PMID: 33532179
- Wang J, Li Q, Yuan J, et al. CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest. J Transl Med 2017; 15(1): 127. doi: 10.1186/s12967-017-1231-7 PMID: 28578693
- Zhang P, Xu B, Gui L, et al. A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer. Biomark Res 2021; 9(1): 24. doi: 10.1186/s40364-021-00271-2 PMID: 33845905
- Chen Z, Xu Y, Gong J, et al. Pyrotinib combined with CDK4/6 inhibitor in HER2-positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients. Clin Transl Med 2020; 10(4): e148. doi: 10.1002/ctm2.148 PMID: 32898333
- Xu XQ, Pan XH, Wang TT, et al. Intrinsic and acquired resistance to CDK4/6 inhibitors and potential overcoming strategies. Acta Pharmacol Sin 2021; 42(2): 171-8. doi: 10.1038/s41401-020-0416-4 PMID: 32504067
- Joshi JJ, Coffey H, Corcoran E, et al. H3B-6527 Is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer Res 2017; 77(24): 6999-7013. doi: 10.1158/0008-5472.CAN-17-1865 PMID: 29247039
- Olmez I, Zhang Y, Manigat L, et al. Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in glioblastoma. Cancer Res 2018; 78(15): 4360-9. doi: 10.1158/0008-5472.CAN-17-3124 PMID: 29844123
- Ohara M, Saito K, Kageyama K, et al. Dual targeting of CDK4/6 and cMET in metastatic uveal melanoma. Cancers (Basel) 2021; 13(5): 13. doi: 10.3390/cancers13051104 PMID: 33806615
- Giordano S, Columbano A. Met as a therapeutic target in HCC: Facts and hopes. J Hepatol 2014; 60(2): 442-52. doi: 10.1016/j.jhep.2013.09.009 PMID: 24045150
- Huang X, Gan G, Wang X, Xu T, Xie W. The HGF-MET axis coordinates liver cancer metabolism and autophagy for chemotherapeutic resistance. Autophagy 2019; 15(7): 1258-79. doi: 10.1080/15548627.2019.1580105 PMID: 30786811
- Lu JW, Lin YM, Chang JG, et al. Clinical implications of deregulated CDK4 and Cyclin D1 expression in patients with human hepatocellular carcinoma. Med Oncol 2013; 30(1): 379. doi: 10.1007/s12032-012-0379-5 PMID: 23292829
- Du Q, Guo X, Wang M, Li Y, Sun X, Li Q. The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J Hematol Oncol 2020; 13(1): 41. doi: 10.1186/s13045-020-00880-8 PMID: 32357912
- Clark AS, Makhlin I, DeMichele A. Setting the pick: Can PI3K inhibitors circumvent CDK4/6 inhibitor resistance? Clin Cancer Res 2021; 27(2): 371-3. doi: 10.1158/1078-0432.CCR-20-3624 PMID: 33144339
- Anders L, Ke N, Hydbring P, et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 2011; 20(5): 620-34. doi: 10.1016/j.ccr.2011.10.001 PMID: 22094256
- Liu G, Sun Y, Ji P, et al. MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol 2014; 233(3): 308-18. doi: 10.1002/path.4348 PMID: 24604117
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