Inhibition of Eukaryotic Initiating Factor eIF4E Overcomes Abemaciclib Resistance in Gastric Cancer.
CDK4/6
eIF4E
gastric cancer
resistance
ribavirin
Journal
Current medical science
ISSN: 2523-899X
Titre abrégé: Curr Med Sci
Pays: China
ID NLM: 101729993
Informations de publication
Date de publication:
Oct 2023
Oct 2023
Historique:
received:
05
11
2022
accepted:
18
07
2023
medline:
23
10
2023
pubmed:
27
9
2023
entrez:
26
9
2023
Statut:
ppublish
Résumé
Aberrant activating mutations in cyclin-dependent kinases 4 and 6 (CDK4/6) are common in various cancers, including gastroesophageal malignancies. Although CDK4/6 inhibitors, such as abemaciclib and palbociclib, have been approved for breast cancer treatment, their effectiveness as a monotherapy remains limited for gastroesophageal tumors. The present study explored the underlying mechanism of abemaciclib resistance. Abemaciclib-resistant gastric cancer cell lines were generated, and the phospho-eukaryotic translation initiation factor 4E (p-eIF4E) and eIF4E expression was compared between resistant and parental cell lines. In order to analyze the role of eIF4E in cell resistance, siRNA knockdown was employed. The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model. The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment. Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition, especially those that were resistant to abemaciclib. Ribavirin, which is an approved anti-viral drug, significantly improved the efficacy of abemaciclib, both in vitro and in vivo, by inhibiting eIF4E. Importantly, ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity. These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer, proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.
Identifiants
pubmed: 37752406
doi: 10.1007/s11596-023-2789-3
pii: 10.1007/s11596-023-2789-3
doi:
Substances chimiques
abemaciclib
60UAB198HK
Eukaryotic Initiation Factor-4E
0
Ribavirin
49717AWG6K
Aminopyridines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
927-934Informations de copyright
© 2023. Huazhong University of Science and Technology.
Références
Bray F, Ferlay J, Soerjomataram I, et al. 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
pubmed: 30207593
Sexton RE, Al Hallak MN, Diab M, et al. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev, 2020,39(4):1179–1203
doi: 10.1007/s10555-020-09925-3
pubmed: 32894370
pmcid: 7680370
Chia NY, Tan P. Molecular classification of gastric cancer. Ann Oncol, 2016,27(5):763–769
doi: 10.1093/annonc/mdw040
pubmed: 26861606
Machlowska J, Baj J, Sitarz M, et al. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci, 2020,21(11):1–20
doi: 10.3390/ijms21114012
Schettini F, De Santo I, Rea CG, et al. CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors. Front Oncol, 2018,8:608
doi: 10.3389/fonc.2018.00608
pubmed: 30631751
pmcid: 6315195
Migliaccio I, Di Leo A, Malorni L. Cyclin-dependent kinase 4/6 inhibitors in breast cancer therapy. Curr Opin Oncol, 2014,26(6):568–575
doi: 10.1097/CCO.0000000000000129
pubmed: 25188473
Mikhail S, Albanese C, Pishvaian MJ. Cyclin-dependent kinase inhibitors and the treatment of gastrointestinal cancers. Am J Pathol, 2015,185(5):1185–1197
doi: 10.1016/j.ajpath.2015.01.008
pubmed: 25747534
pmcid: 5707194
Karasic TB, O’Hara MH, Teitelbaum UR, et al. Phase II Trial of Palbociclib in Patients with Advanced Esophageal or Gastric Cancer. Oncologist, 2020,25(12):e1864–e1868
doi: 10.1634/theoncologist.2020-0681
pubmed: 32692450
Romagnoli A, D’Agostino M, Ardiccioni C, et al. Control of the eIF4E activity: structural insights and pharmacological implications. Cell Mol Life Sci, 2021,78(21–22):6869–6885
doi: 10.1007/s00018-021-03938-z
pubmed: 34541613
pmcid: 8558276
Larsson O, Li S, Issaenko OA, et al. 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, 2007,67(14):6814–6824
doi: 10.1158/0008-5472.CAN-07-0752
pubmed: 17638893
Zheng J, Li X, Zhang C, et al. eIF4E Overexpression Is Associated with Poor Prognoses of Ovarian Cancer. Anal Cell Pathol (Amst), 2020,2020:8984526
pubmed: 33489719
Lu J, Zang H, Zheng H, et al. Overexpression of p-Akt, p-mTOR and p-eIF4E proteins associates with metastasis and unfavorable prognosis in non-small cell lung cancer. PLoS One, 2020,15(2):e0227768
doi: 10.1371/journal.pone.0227768
pubmed: 32023262
pmcid: 7001968
Xu T, Zong Y, Peng L, et al. Overexpression of eIF4E in colorectal cancer patients is associated with liver metastasis. Onco Targets Ther, 2016,9:815–822
pubmed: 26929650
pmcid: 4767060
Martinez-Saez E, Peg V, Ortega-Aznar A, et al. peIF4E as an independent prognostic factor and a potential therapeutic target in diffuse infiltrating astrocytomas. Cancer Med, 2016,5(9):2501–2512
doi: 10.1002/cam4.817
pubmed: 27440383
pmcid: 5055163
Ge Y, Wu Q, Ma G, et al. Hypermethylation of EIF4E promoter is associated with early onset of gastric cancer. Carcinogenesis, 2018,39(1):66–71
doi: 10.1093/carcin/bgx110
pubmed: 29342273
Tapia O, Riquelme I, Leal P, et al. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch, 2014,465(1):25–33
doi: 10.1007/s00428-014-1588-4
pubmed: 24844205
Chen CN, Hsieh FJ, Cheng YM, et al. Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol, 2004,86(1):22–27
doi: 10.1002/jso.20037
pubmed: 15048676
Liang S, Guo R, Zhang Z, et al. Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth. Oncol Rep, 2013,29(6):2422–2430
doi: 10.3892/or.2013.2397
pubmed: 23588929
Graff JR, Konicek BW, Carter JH, et al. Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Cancer Res, 2008,68(3):631–634
doi: 10.1158/0008-5472.CAN-07-5635
pubmed: 18245460
Hu K, Zhang J, Yu M, et al. Inhibition of Mnk-eIF4E pathway sensitizes the efficacy to chemotherapy in anaplastic thyroid cancer. Future Oncol, 2017,13(6):489–498
doi: 10.2217/fon-2016-0320
pubmed: 27785922
Grzmil M, Seebacher J, Hess D, et al. Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy. Cell Signal, 2016,28(9):1412–1421
doi: 10.1016/j.cellsig.2016.06.005
pubmed: 27289018
Borden KL, Culjkovic-Kraljacic B. Ribavirin as an anticancer therapy: acute myeloid leukemia and beyond? Leuk Lymphoma, 2010,51(10):1805–1815
doi: 10.3109/10428194.2010.496506
pubmed: 20629523
pmcid: 2950216
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res, 2010,70(2):440–446
doi: 10.1158/0008-5472.CAN-09-1947
pubmed: 20068163
Culjkovic-Kraljacic B, Fernando TM, Marullo R, et al. Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas. Blood, 2016,127(7):858–868
doi: 10.1182/blood-2015-05-645069
pubmed: 26603836
pmcid: 4760090
Liu Y, Zhao Y, Han C, et al. Expression of CDK6 in Stomach Cancer and the Effect of CDK4/6 Inhibitor PD-0332991 on the Function of Stomach Cancer Cells. Comput Math Methods Med, 2022,2022:2402567
pubmed: 35535229
pmcid: 9078806
Valenzuela CA, Vargas L, Martinez V, et al. Palbociclib-induced autophagy and senescence in gastric cancer cells. Exp Cell Res, 2017,360(2):390–396
doi: 10.1016/j.yexcr.2017.09.031
pubmed: 28947133
Bae HJ, Kang SK, Kwon WS, et al. p16 methylation is a potential predictive marker for abemaciclib sensitivity in gastric cancer. Biochem Pharmacol, 2021,183:114320
doi: 10.1016/j.bcp.2020.114320
pubmed: 33161023
Min A, Kim JE, Kim YJ, et al. Cyclin E overexpression confers resistance to the CDK4/6 specific inhibitor palbociclib in gastric cancer cells. Cancer Lett, 2018,430:123–132
doi: 10.1016/j.canlet.2018.04.037
pubmed: 29729292
Zhang Y, He LJ, Huang LL, et al. Oncogenic PAX6 elicits CDK4/6 inhibitor resistance by epigenetically inactivating the LATS2-Hippo signaling pathway. Clin Transl Med, 2021,11(8):e503
doi: 10.1002/ctm2.503
pubmed: 34459131
pmcid: 8382979
Zhu Y, Wang C, Li M, et al. Targeting of MNK/eIF4E overcomes chemoresistance in cervical cancer. J Pharm Pharmacol, 2021,73(10):1418–1426
doi: 10.1093/jpp/rgab094
pubmed: 34254647
Liu T, Li R, Zhao H, et al. eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma. Oncotarget, 2016,7(41):66851–66864
doi: 10.18632/oncotarget.11694
pubmed: 27588477
pmcid: 5341842
Fischer PD, Papadopoulos E, Dempersmier JM, et al. A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders. Eur J Med Chem, 2021,219:113435
doi: 10.1016/j.ejmech.2021.113435
pubmed: 33892272
pmcid: 8846605
Volpon L, Osborne MJ, Borden KLB. Biochemical and Structural Insights into the Eukaryotic Translation Initiation Factor eIF4E. Curr Protein Peptide Sci, 2019,20(6):525–535
doi: 10.2174/1389203720666190110142438
Kentsis A, Topisirovic I, Culjkovic B, et al. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci USA, 2004,101(52):18105–18110
doi: 10.1073/pnas.0406927102
pubmed: 15601771
pmcid: 539790
Pettersson F, Yau C, Dobocan MC, et al. Ribavirin treatment effects on breast cancers overexpressing eIF4E, a biomarker with prognostic specificity for luminal B-type breast cancer. Clin Cancer Res, 2011,17(9):2874–2884
doi: 10.1158/1078-0432.CCR-10-2334
pubmed: 21415224
pmcid: 3086959
Bodenheimer HC Jr, Lindsay KL, Davis GL, et al. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology, 1997,26(2):473–477
doi: 10.1002/hep.510260231
pubmed: 9252161
Assouline S, Culjkovic B, Cocolakis E, et al. Molecular targeting of the oncogene eIF4E in acute myeloid leukemia (AML): a proof-of-principle clinical trial with ribavirin. Blood, 2009,114(2):257–260
doi: 10.1182/blood-2009-02-205153
pubmed: 19433856