Biomolecules & Therapeutics

  • 제32권5호
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  • Pages.577-581
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  • 2024
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Gilteritinib Reduces FLT3 Expression in Acute Myeloid Leukemia Cells

  • Thi Lam Thai (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University) ;
  • Sun-Young Han (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University)
  • 투고 : 2023.12.07
  • 심사 : 2023.12.19
  • 발행 : 2024.09.01
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초록

Acute myeloid leukemia (AML) is a genetically diverse and challenging malignancy, with mutations in the FLT3 gene being particularly common and deleterious. Gilteritinib, a potent FLT3 inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib was developed based on its inhibitory activity against FLT3 kinase, it is important to understand the precise mechanisms of its antileukemic activity in managing drug resistance and discovering biomarkers. This study was designed to elucidate the effect of gilteritinib on the FLT3 expression level. The results showed that gilteritinib induced a dose-dependent decrease in both FLT3 phosphorylation and expression. This reduction was particularly pronounced after 48 h of treatment. The decrease in FLT3 expression was found to be independent of changes in FLT3 mRNA transcription, suggesting post-transcriptional regulatory mechanisms. Further studies were performed in various AML cell lines and cells with both FLT3 wild-type and FLT3 mutant exhibited FLT3 reduction by gilteritinib treatment. In addition, other FLT3 inhibitors were evaluated for their ability to reduce FLT3 expression. Other FLT3 inhibitors, midostaurin, crenolanib, and quizartinib, also reduced FLT3 expression, consistent with the effect of gilteritinib. These findings hold great promise for optimizing gilteritinib treatment in AML patients. However, it is important to recognize that further research is warranted to gain a full understanding of these mechanisms and their clinical implications in the context of FLT3 reduction.

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과제정보

This research was funded by the National Research Foundation, Government of Korea, grant number 2021R1A2C1007790 (S-Y.H.).

참고문헌

  1. Acharya, B., Saha, D., Armstrong, D., Lakkaniga, N. R. and Frett, B. (2022) FLT3 inhibitors for acute myeloid leukemia: successes, defeats, and emerging paradigms. RSC Med. Chem. 13, 798-816. https://doi.org/10.1039/D2MD00067A
  2. Ampasavate, C., Jutapakdee, W., Phongpradist, R., Tima, S., Tantiworawit, A., Charoenkwan, P., Chinwong, D. and Anuchapreeda, S. (2019) FLT3, a prognostic biomarker for acute myeloid leukemia (AML): quantitative monitoring with a simple anti-FLT3 interaction and flow cytometric method. J. Clin. Lab. Anal. 33, e22859.
  3. Cao, S., Ma, L., Liu, Y., Wei, M., Yao, Y., Li, C., Wang, R., Liu, N., Dong, Z., Li, X., Li, M., Wang, X., Yang, C. and Yang, G. (2021) Proteolysis-targeting chimera (PROTAC) modification of dovitinib enhances the antiproliferative effect against FLT3-ITD-positive acute myeloid leukemia cells. J. Med. Chem. 64, 16497-16511. https://doi.org/10.1021/acs.jmedchem.1c00996
  4. Chen, Y., Yuan, X., Tang, M., Shi, M., Yang, T., Liu, K., Deng, D. and Chen, L. (2022) Degrading FLT3-ITD protein by proteolysis targeting chimera (PROTAC). Bioorg. Chem. 119, 105508.
  5. Cortes, J., Perl, A. E., Dohner, H., Kantarjian, H., Martinelli, G., Kovacsovics, T., Rousselot, P., Steffen, B., Dombret, H., Estey, E., Strickland, S., Altman, J. K., Baldus, C. D., Burnett, A., Kramer, A., Russell, N., Shah, N. P., Smith, C. C., Wang, E. S., Ifrah, N., Gammon, G., Trone, D., Lazzaretto, D. and Levis, M. (2018) Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 19, 889-903. https://doi.org/10.1016/S1470-2045(18)30240-7
  6. Daver, N., Schlenk, R. F., Russell, N. H. and Levis, M. J. (2019) Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia 33, 299-312. https://doi.org/10.1038/s41375-018-0357-9
  7. DiNardo, C. D. and Cortes, J. E. (2016) Mutations in AML: prognostic and therapeutic implications. Hematology Am. Soc. Hematol. Educ. Program 2016, 348-355. https://doi.org/10.1182/asheducation-2016.1.348
  8. Galanis, A., Ma, H., Rajkhowa, T., Ramachandran, A., Small, D., Cortes, J. and Levis, M. (2014) Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 123, 94-100. https://doi.org/10.1182/blood-2013-10-529313
  9. Gunawardane, R. N., Nepomuceno, R. R., Rooks, A. M., Hunt, J. P., Ricono, J. M., Belli, B. and Armstrong, R. C. (2013) Transient exposure to quizartinib mediates sustained inhibition of FLT3 signaling while specifically inducing apoptosis in FLT3-activated leukemia cells. Mol. Cancer Ther. 12, 438-447. https://doi.org/10.1158/1535-7163.MCT-12-0305
  10. Katagiri, S., Furuya, N., Akahane, D., Chi, S., Minami, Y., Harada, Y., Harada, H. and Gotoh, A. (2023) Gilteritinib affects the selection of dominant clones in clonal hematopoiesis: sequential genetic analysis of an FLT3-ITD positive AML patient with long-term gilteritinib therapy. Onco Targets Ther. 16, 571-576. https://doi.org/10.2147/OTT.S417137
  11. Katayama, K., Noguchi, K. and Sugimoto, Y. (2018) Heat shock protein 90 inhibitors overcome the resistance to Fms-like tyrosine kinase 3 inhibitors in acute myeloid leukemia. Oncotarget 9, 34240-34258. https://doi.org/10.18632/oncotarget.26045
  12. Larrue, C., Saland, E., Boutzen, H., Vergez, F., David, M., Joffre, C., Hospital, M. A., Tamburini, J., Delabesse, E., Manenti, S., Sarry, J. E. and Recher, C. (2016) Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells. Blood 127, 882-892. https://doi.org/10.1182/blood-2015-05-646497
  13. Levis, M. (2013) FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am. Soc. Hematol. Educ. Program 2013, 220-226. https://doi.org/10.1182/asheducation-2013.1.220
  14. Levis, M. and Perl, A. E. (2020) Gilteritinib: potent targeting of FLT3 mutations in AML. Blood Adv. 4, 1178-1191. https://doi.org/10.1182/bloodadvances.2019000174
  15. Ly, B. T., Chi, H. T., Yamagishi, M., Kano, Y., Hara, Y., Nakano, K., Sato, Y. and Watanabe, T. (2013) Inhibition of FLT3 expression by green tea catechins in FLT3 mutated-AML cells. PLoS One 8, e66378.
  16. Martinez-Gutierrez, L. N., Burgher, B. C., Glynias, M. J., Alvarado, D., Griffiths, E. A., Glenn, S. T. and Sung, P. J. (2023) Evaluation of hypereosinophilia in a case of FLT3-mutant acute myeloid leukemia treated with gilteritinib. Cold Spring Harb. Mol. Case Stud. 9, a006279.
  17. Meshinchi, S. and Appelbaum, F. R. (2009) Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin. Cancer Res. 15, 4263-4269. https://doi.org/10.1158/1078-0432.CCR-08-1123
  18. Minami, Y., Kiyoi, H., Yamamoto, Y., Yamamoto, K., Ueda, R., Saito, H. and Naoe, T. (2002) Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 16, 1535-1540. https://doi.org/10.1038/sj.leu.2402558
  19. Mori, M., Kaneko, N., Ueno, Y., Yamada, M., Tanaka, R., Saito, R., Shimada, I., Mori, K. and Kuromitsu, S. (2017) Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest. New Drugs 35, 556-565. https://doi.org/10.1007/s10637-017-0470-z
  20. Ohoka, N., Suzuki, M., Uchida, T., Tsuji, G., Tsukumo, Y., Yoshida, M., Inoue, T., Demizu, Y., Ohki, H. and Naito, M. (2022) Development of gilteritinib-based chimeric small molecules that potently induce degradation of FLT3-ITD protein. ACS Med. Chem. Lett. 13, 1885-1891. https://doi.org/10.1021/acsmedchemlett.2c00402
  21. Pollyea, D. A., Altman, J. K., Assi, R., Bixby, D., Fathi, A. T., Foran, J. M., Gojo, I., Hall, A. C., Jonas, B. A., Kishtagari, A., Lancet, J., Maness, L., Mangan, J., Mannis, G., Marcucci, G., Mims, A., Moriarty, K., Mustafa Ali, M., Neff, J., Nejati, R., Olin, R., Percival, M. E., Perl, A., Przespolewski, A., Rao, D., Ravandi, F., Shallis, R., Shami, P. J., Stein, E., Stone, R. M., Sweet, K., Thota, S., Uy, G., Vachhani, P., Cassara, C. J., Freedman-Cass, D. A. and Stehman, K. (2023) Acute myeloid leukemia, version 3.2023, NCCN Clinical Practice Guidelines in oncology. J. Natl. Compr. Canc. Netw. 21, 503-513. https://doi.org/10.6004/jnccn.2023.0025
  22. Quentmeier, H., Reinhardt, J., Zaborski, M. and Drexler, H. G. (2003) FLT3 mutations in acute myeloid leukemia cell lines. Leukemia 17, 120-124. https://doi.org/10.1038/sj.leu.2402740
  23. Shimada, A. (2019) Hematological malignancies and molecular targeting therapy. Eur. J. Pharmacol. 862, 172641.
  24. Stone, R. M., Mandrekar, S. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., Thiede, C., Prior, T. W., Dohner, K., Marcucci, G., Lo-Coco, F., Klisovic, R. B., Wei, A., Sierra, J., Sanz, M. A., Brandwein, J. M., de Witte, T., Niederwieser, D., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Krauter, J., Schlenk, R. F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Larson, R. A. and Dohner, H. (2017) Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N. Engl. J. Med. 377, 454-464. https://doi.org/10.1056/NEJMoa1614359
  25. Tao, S. D., Wang, C. L., Chen, Y., Deng, Y., Song, L. X., Shi, Y. Y., Ling, L. L., Ding, B. H., He, Z. M. and Yu, L. (2019) Prognosis and outcome of patients with acute myeloid leukemia based on FLT3-ITD mutation with or without additional abnormal cytogenetics. Oncol. Lett. 18, 6766-6774. https://doi.org/10.3892/ol.2019.11051
  26. Wang, L. N., Tang, Y. L., Zhang, Y. C., Zhang, Z. H., Liu, X. J., Ke, Z. Y., Li, Y., Tan, H. Z., Huang, L. B. and Luo, X. Q. (2017) Arsenic trioxide and all-trans-retinoic acid selectively exert synergistic cytotoxicity against FLT3-ITD AML cells via co-inhibition of FLT3 signaling pathways. Leuk. Lymphoma 58, 2426-2438. https://doi.org/10.1080/10428194.2017.1289522
  27. Weisberg, E., Meng, C., Case, A. E., Sattler, M., Tiv, H. L., Gokhale, P. C., Buhrlage, S. J., Liu, X., Yang, J., Wang, J., Gray, N., Stone, R. M., Adamia, S., Dubreuil, P., Letard, S. and Griffin, J. D. (2019) Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies. Br. J. Haematol. 187, 488-501. https://doi.org/10.1111/bjh.16092
  28. Zhang, H., Savage, S., Schultz, A. R., Bottomly, D., White, L., Segerdell, E., Wilmot, B., McWeeney, S. K., Eide, C. A., Nechiporuk, T., Carlos, A., Henson, R., Lin, C., Searles, R., Ho, H., Lam, Y. L., Sweat, R., Follit, C., Jain, V., Lind, E., Borthakur, G., GarciaManero, G., Ravandi, F., Kantarjian, H. M., Cortes, J., Collins, R., Buelow, D. R., Baker, S. D., Druker, B. J. and Tyner, J. W. (2019) Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat. Commun. 10, 244.
  29. Zhao, J., Song, Y. and Liu, D. (2019) Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. Biomark. Res. 7, 19.
  30. Zhao, J. C., Agarwal, S., Ahmad, H., Amin, K., Bewersdorf, J. P. and Zeidan, A. M. (2022) A review of FLT3 inhibitors in acute myeloid leukemia. Blood Rev. 52, 100905.