Abstract
Background
To investigate the effects of osimertinib on hepatocellular carcinoma (HCC) and angiogenesis, and its combinatory effects with venetoclax in HCC.
Methods
Viability was assessed by flow cytometry of Annexin V in multiple HCC cell lines after drug treatment. In vitro angiogenesis assay was performed using primary human liver tumor associated endothelial cell (HLTEC). HCC-bearing model was generated by subcutaneous implantation of Hep3B cells to investigate the efficacy of osimertinib alone and its combination with venetoclax.
Results
Osimertinib significantly induced apoptosis in a panel of HCC cell lines regardless of EGFR expression level. It inhibited capillary network formation and induced apoptosis in HLTEC. Using HCC xenograft mouse model, we further showed that osimertinib at non-toxic dose inhibited tumor growth by ~ 50% and remarkably decreased blood vessel in tumor. Mechanism studies demonstrated that osimertinib acted on HCC cells in an EGFR-independent manner. It decreased level of VEGF and Mcl-1 in HCC cells via suppressed phosphorylation of eIF4E, thus leading to inhibition of eIF4E-mediated translation. Mcl-1 overexpression reversed pro-apoptotic effect of osimertinib, suggesting an important role of Mcl-1 in osimertinib’s action in HCC cells. Of note, the combination of osimertinib and venetoclax achieved approximately complete HCC cell death and tumor growth in mice.
Conclusions
We provide pre-clinical evidence that osimertinib is a promising candidate for the treatment of HCC via targeting tumor cells and angiogenesis. The combination of osimertinib and venetoclax is synergistic in inhibiting HCC.
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Data availability
Data will be made available upon reasonable request the corresponding author.
References
Algarin EM, Diaz-Tejedor A, Mogollon P, Hernandez-Garcia S, Corchete LA, San-Segundo L et al (2020) Preclinical evaluation of the simultaneous inhibition of MCL-1 and BCL-2 with the combination of S63845 and venetoclax in multiple myeloma. Haematologica 105:e116–e120. https://doi.org/10.3324/haematol.2018.212308. (PMID:31320555)
Bertino EM, Gentzler RD, Clifford S, Kolesar J, Muzikansky A, Haura EB et al (2021) Phase IB study of osimertinib in combination with navitoclax in EGFR-mutant NSCLC following resistance to initial EGFR therapy (ETCTN 9903). Clin Cancer Res 27:1604–1611. https://doi.org/10.1158/1078-0432.CCR-20-4084. (PMID:33376097)
Bertuccio P, Turati F, Carioli G, Rodriguez T, La Vecchia C, Malvezzi M et al (2017) Global trends and predictions in hepatocellular carcinoma mortality. J Hepatol 67:302–309. https://doi.org/10.1016/j.jhep.2017.03.011. (PMID:28336466)
Chen C, Wang G (2015) Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy. World J Hepatol 7:1964–1970. https://doi.org/10.4254/wjh.v7.i15.1964. (PMID:26244070)
Chen S, Cao Q, Wen W, Wang H (2019) Targeted therapy for hepatocellular carcinoma: challenges and opportunities. Cancer Lett 460:1–9. https://doi.org/10.1016/j.canlet.2019.114428. (PMID:31207320)
Chen C, Cheng CD, Wu H, Wang ZW, Wang L, Jiang ZR et al (2021) Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway. Acta Pharmacol Sin 42:108–114. https://doi.org/10.1038/s41401-020-0418-2. (PMID:32398685)
Culjkovic-Kraljacic B, Skrabanek L, Revuelta MV, Gasiorek J, Cowling VH, Cerchietti L et al (2020) The eukaryotic translation initiation factor eIF4E elevates steady-state m(7)G capping of coding and noncoding transcripts. Proc Natl Acad Sci USA 117:26773–26783. https://doi.org/10.1073/pnas.2002360117. (PMID:33055213)
Hirschfield H, Bian CB, Higashi T, Nakagawa S, Zeleke TZ, Nair VD et al (2018) In vitro modeling of hepatocellular carcinoma molecular subtypes for anti-cancer drug assessment. Exp Mol Med 50:e419. https://doi.org/10.1038/emm.2017.164. (PMID:29303513)
Huang A, Yang XR, Chung WY, Dennison AR, Zhou J (2020) Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther 5:146. https://doi.org/10.1038/s41392-020-00264-x. (PMID:32782275)
Larsson O, Li S, Issaenko OA, Avdulov S, Peterson M, Smith K et al (2007) Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res 67:6814–6824. https://doi.org/10.1158/0008-5472.CAN-07-0752. (PMID:17638893)
Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M (2019) Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer 121:725–737. https://doi.org/10.1038/s41416-019-0573-8. (PMID:31564718)
Liu Z, Gao W (2020) Synergistic effects of Bcl-2 inhibitors with AZD9291 on overcoming the acquired resistance of AZD9291 in H1975 cells. Arch Toxicol 94:3125–3136. https://doi.org/10.1007/s00204-020-02816-0. (PMID:32577785)
Liu Y, Calmel C, Desbois-Mouthon C, Sobczak-Thepot J, Karaiskou A, Praz F (2020) Regulation of the EGFR/ErbB signalling by clathrin in response to various ligands in hepatocellular carcinoma cell lines. J Cell Mol Med 24:8091–8102. https://doi.org/10.1111/jcmm.15440. (PMID:32515546)
Lu Y, Bian D, Zhang X, Zhang H, Zhu Z (2021) Inhibition of Bcl-2 and Bcl-xL overcomes the resistance to the third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer. Mol Med Rep. https://doi.org/10.3892/mmr.2020.11686. (PMID:33200796)
Luedtke DA, Niu X, Pan Y, Zhao J, Liu S, Edwards H et al (2017) Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal Transduct Target Ther 2:17012. https://doi.org/10.1038/sigtrans.2017.12. (PMID:29263915)
Ma J, Zhao S, Qiao X, Knight T, Edwards H, Polin L et al (2019) Inhibition of Bcl-2 synergistically enhances the antileukemic activity of midostaurin and gilteritinib in preclinical models of FLT3-mutated acute myeloid leukemia. Clin Cancer Res 25:6815–6826. https://doi.org/10.1158/1078-0432.CCR-19-0832. (PMID:31320594)
Madri JA, Pratt BM (1986) Endothelial cell-matrix interactions: in vitro models of angiogenesis. J Histochem Cytochem 34:85–91 (PMID:2416801)
Moawad AW, Szklaruk J, Lall C, Blair KJ, Kaseb AO, Kamath A et al (2020) Angiogenesis in hepatocellular carcinoma; pathophysiology, targeted therapy, and role of imaging. J Hepatocell Carcinoma 7:77–89. https://doi.org/10.2147/JHC.S224471. (PMID:32426302)
Moon H, Ro SW (2021) MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers (basel). https://doi.org/10.3390/cancers13123026. (PMID:34204242)
Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M et al (2019) The role of angiogenesis in hepatocellular carcinoma. Clin Cancer Res 25:912–920. https://doi.org/10.1158/1078-0432.CCR-18-1254. (PMID:30274981)
Niu X, Zhao J, Ma J, Xie C, Edwards H, Wang G et al (2016) Binding of released Bim to Mcl-1 is a mechanism of intrinsic resistance to ABT-199 which can be overcome by combination with daunorubicin or cytarabine in AML Cells. Clin Cancer Res 22:4440–4451. https://doi.org/10.1158/1078-0432.CCR-15-3057. (PMID:27103402)
Sullivan I, Planchard D (2016) Osimertinib in the treatment of patients with epidermal growth factor receptor T790M mutation-positive metastatic non-small cell lung cancer: clinical trial evidence and experience. Ther Adv Respir Dis 10:549–565. https://doi.org/10.1177/1753465816670498. (PMID:27784815)
Tamura T, Takagi Y, Okubo H, Yamaguchi S, Kikkawa Y, Hashimoto I et al (2017) Plasma concentration of osimertinib in a non-small cell lung cancer patient with chronic renal failure undergoing hemodialysis. Lung Cancer 112:225–226. https://doi.org/10.1016/j.lungcan.2017.07.007. (PMID:28709627)
Tran NH, Munoz S, Thompson S, Hallemeier CL, Bruix J (2022) Hepatocellular carcinoma downstaging for liver transplantation in the era of systemic combined therapy with anti-VEGF/TKI and immunotherapy. Hepatology. https://doi.org/10.1002/hep.32613. (PMID:35765265)
Wang Y, Zhang M, Gong Y, Wu Q, Zhang L, Jiao S (2021) Bioinformatic analysis of hepatocellular carcinoma cell lines to the efficacy of nimotuzumab. Int J Gen Med 14:2611–2621. https://doi.org/10.2147/IJGM.S312770. (PMID:34168487)
Zhang KL, Shen QQ, Fang YF, Sun YM, Ding J, Chen Y (2019) AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition. Acta Pharmacol Sin 40:1587–1595. https://doi.org/10.1038/s41401-019-0248-2. (PMID:31171828)
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Funding
This work was supported by research grants provided by Health Commission of Hubei Province (Grant No. WJ2019F094).
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Qiaoxin Huang and Dongang Zhan designed the concept, performed experiment and wrote the manuscript altogether. Shengsong He performed the experiment.
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Animal studies were approved by the Institutional Animal Care and Use Committee of Hubei University of Arts and Science and conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (Publication No. 85–23, revised 1996).
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Huang, Q., He, S. & Zhan, D. Osimertinib is a dual inhibitor of hepatocellular carcinoma and angiogenesis in an EGFR-independent manner, and synergizes with venetoclax. J Cancer Res Clin Oncol 149, 10727–10735 (2023). https://doi.org/10.1007/s00432-023-04926-5
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DOI: https://doi.org/10.1007/s00432-023-04926-5