Reports of Biochemistry
and Molecular Biology
Sun, Dec 22, 2024
[Archive]
Volume 12, Issue 1 (Vol.12 No.1 Apr 2023)
rbmb.net 2023, 12(1): 74-82 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Fan Z, Zhang L, Zhang S, Liu A, Li S, Cao X, et al . Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib. rbmb.net 2023; 12 (1) :74-82
URL: http://rbmb.net/article-1-1102-en.html
URL: http://rbmb.net/article-1-1102-en.html
Zhaoyang Fan 
, Liangying Zhang , Shaoting Zhang , Anbu Liu , Shujing Li , Xu Cao , Jinhai Tian , Sien Zhao , Jianmin Sun *
, Liangying Zhang , Shaoting Zhang , Anbu Liu , Shujing Li , Xu Cao , Jinhai Tian , Sien Zhao , Jianmin Sun *
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
Abstract: (1546 Views)
Background: Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation.
Methods: The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot.
Results: We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors.
Conclusions: Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.
Methods: The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot.
Results: We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors.
Conclusions: Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.
Type of Article: Original Article |
Subject:
Molecular Biology
Received: 2022/11/27 | Accepted: 2022/12/19 | Published: 2023/08/15
Received: 2022/11/27 | Accepted: 2022/12/19 | Published: 2023/08/15
References
1. Tsai M, Valent P, Galli SJ. KIT as a master regulator of the mast cell lineage. The Journal of allergy and clinical immunology. 2022;149(6):1845-54. [DOI:10.1016/j.jaci.2022.04.012] [PMID] [PMCID]
2. Foster BM, Zaidi D, Young TR, Mobley ME, Kerr BA. CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance. Biomedicines. 2018;6(1). [DOI:10.3390/biomedicines6010031] [PMID] [PMCID]
3. Lennartsson J, Ronnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiological reviews. 2012;92(4):1619-49. [DOI:10.1152/physrev.00046.2011] [PMID]
4. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-80. [DOI:10.1126/science.279.5350.577] [PMID]
5. Tarn C, Merkel E, Canutescu AA, Shen W, Skorobogatko Y, Heslin MJ, et al. Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling. Clinical cancer research : an official journal of the American Association for Cancer Research. 2005;11(10):3668-77. [DOI:10.1158/1078-0432.CCR-04-2515] [PMID]
6. Steigen SE, Eide TJ, Wasag B, Lasota J, Miettinen M. Mutations in gastrointestinal stromal tumors--a population-based study from Northern Norway. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2007;115(4):289-98. [DOI:10.1111/j.1600-0463.2007.apm_587.x] [PMID]
7. Gomes AL, Bardales RH, Milanezi F, Reis RM, Schmitt F. Molecular analysis of c-Kit and PDGFRA in GISTs diagnosed by EUS. American journal of clinical pathology. 2007;127(1):89-96. [DOI:10.1309/M1EC8JE9ACAMJACU] [PMID]
8. Akin C, Arock M, Valent P. Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet? The Journal of allergy and clinical immunology. 2022;149(6):1912-8. [DOI:10.1016/j.jaci.2022.04.020] [PMID]
9. Meng D, Carvajal RD. KIT as an Oncogenic Driver in Melanoma: An Update on Clinical Development. American journal of clinical dermatology. 2019;20(3):315-23. [DOI:10.1007/s40257-018-0414-1] [PMID]
10. Biermann K, Goke F, Nettersheim D, Eckert D, Zhou H, Kahl P, et al. c-KIT is frequently mutated in bilateral germ cell tumours and down-regulated during progression from intratubular germ cell neoplasia to seminoma. The Journal of pathology. 2007;213(3):311-8. [DOI:10.1002/path.2225] [PMID]
11. Shen H, Shih J, Hollern DP, Wang L, Bowlby R, Tickoo SK, et al. Integrated Molecular Characterization of Testicular Germ Cell Tumors. Cell reports. 2018;23(11):3392-406. [DOI:10.1016/j.celrep.2018.05.039] [PMID] [PMCID]
12. Zhu G, Shi J, Zhang S, Guo Y, Huang L, Zhao H, et al. Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib. Cell & bioscience. 2020;10:16. [DOI:10.1186/s13578-020-0377-9] [PMID] [PMCID]
13. Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003;21(23):4342-9. [DOI:10.1200/JCO.2003.04.190] [PMID]
14. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-38. [DOI:10.1016/S0140-6736(06)69446-4] [PMID]
15. Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302. [DOI:10.1016/S0140-6736(12)61857-1] [PMID]
16. Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, Gelderblom H, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Oncology. 2020;21(7):923-34. [DOI:10.1016/S1470-2045(20)30168-6] [PMID]
17. Krystal GW, DeBerry CS, Linnekin D, Litz J. Lck associates with and is activated by Kit in a small cell lung cancer cell line: inhibition of SCF-mediated growth by the Src family kinase inhibitor PP1. Cancer research. 1998;58(20):4660-6.
18. Timokhina I, Kissel H, Stella G, Besmer P. Kit signaling through PI 3-kinase and Src kinase pathways: an essential role for Rac1 and JNK activation in mast cell proliferation. The EMBO journal. 1998;17(21):6250-62. [DOI:10.1093/emboj/17.21.6250] [PMID] [PMCID]
19. Voytyuk O, Lennartsson J, Mogi A, Caruana G, Courtneidge S, Ashman LK, et al. Src family kinases are involved in the differential signaling from two splice forms of c-Kit. The Journal of biological chemistry. 2003;278(11):9159-66. [DOI:10.1074/jbc.M211726200] [PMID]
20. Blume-Jensen P, Siegbahn A, Stabel S, Heldin CH, Ronnstrand L. Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C. The EMBO journal. 1993;12(11):4199-209. [DOI:10.1002/j.1460-2075.1993.tb06104.x] [PMID] [PMCID]
21. Chen LL, Trent JC, Wu EF, Fuller GN, Ramdas L, Zhang W, et al. A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer research. 2004;64(17):5913-9. [DOI:10.1158/0008-5472.CAN-04-0085] [PMID]
22. Sakurama K, Noma K, Takaoka M, Tomono Y, Watanabe N, Hatakeyama S, et al. Inhibition of focal adhesion kinase as a potential therapeutic strategy for imatinib-resistant gastrointestinal stromal tumor. Molecular cancer therapeutics. 2009;8(1):127-34. [DOI:10.1158/1535-7163.MCT-08-0884] [PMID]
23. Tarn C, Rink L, Merkel E, Flieder D, Pathak H, Koumbi D, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(24):8387-92. [DOI:10.1073/pnas.0803383105] [PMID] [PMCID]
24. Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes, chromosomes & cancer. 2008;47(10):853-9. [DOI:10.1002/gcc.20589] [PMID] [PMCID]
25. Bosbach B, Rossi F, Yozgat Y, Loo J, Zhang JQ, Berrozpe G, et al. Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(40):E8448-E57. [DOI:10.1073/pnas.1711449114] [PMID] [PMCID]
26. Ran L, Sirota I, Cao Z, Murphy D, Chen Y, Shukla S, et al. Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth. Cancer discovery. 2015;5(3):304-15. [DOI:10.1158/2159-8290.CD-14-0985] [PMID] [PMCID]
27. Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(23):10560-4. [DOI:10.1073/pnas.92.23.10560] [PMID] [PMCID]
28. Reiter A, Gotlib J, Alvarez-Twose I, Radia DH, Lubke J, Bobbili PJ, et al. Efficacy of avapritinib versus best available therapy in the treatment of advanced systemic mastocytosis. Leukemia. 2022;36(8):2108-20. [DOI:10.1038/s41375-022-01615-z] [PMID] [PMCID]
29. Punekar SR, Velcheti V, Neel BG, Wong KK. The current state of the art and future trends in RAS-targeted cancer therapies. Nature reviews Clinical oncology. 2022;19(10):637-55. [DOI:10.1038/s41571-022-00671-9] [PMID] [PMCID]
30. Molina-Arcas M, Samani A, Downward J. Drugging the Undruggable: Advances on RAS Targeting in Cancer. Genes. 2021;12(6). [DOI:10.3390/genes12060899] [PMID] [PMCID]
31. Ahearn IM, Haigis K, Bar-Sagi D, Philips MR. Regulating the regulator: post-translational modification of RAS. Nature reviews Molecular cell biology. 2011;13(1):39-51. [DOI:10.1038/nrm3255] [PMID] [PMCID]
32. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ, et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med. 1995;1(8):792-7. [DOI:10.1038/nm0895-792] [PMID]
Send email to the article author
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
