Abivertinib synergistically strengthens the anti‐leukemia activity of venetoclax in acute myeloid leukemia in a BTK‐dependent manner
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B‐cell lymphoma 2 (BCL‐2), a crucial member of the anti‐apoptotic BCL‐2 family, is frequently dysregulated in cancer and plays an important role in acute myeloid leukemia (AML). Venetoclax is a highly selective BCL‐2 inhibitor that has been approved by the FDA for treating elderly AML patients. However, the emergence of resistance after long‐term treatment emphasizes the need for a deeper understanding of the potential mechanisms of resistance and effective rescue methods. By using RNA‐seq analysis in two human AML cohorts made up of three patients with complete remission and three patients without remission after venetoclax treatment, we identified that upregulation of BTK enabled AML blast resistance to venetoclax. Interestingly, we found that abivertinib, an oral BTK inhibitor, could synergize with venetoclax to inhibit the proliferation of primary AML cells and cell lines. It is worth noting that the combination of the two effectively enhanced the sensitivity of two AML patients (AML#3 and AML#12) to venetoclax. In this study, we demonstrated that combined use of the two drugs can synergistically inhibit the colony‐forming capacity of AML cells, arrest the AML cell cycle in the G0/G1 phase, and inhibit the BCL‐2 anti‐apoptotic family protein, activating the caspase family to induce apoptosis. Mechanistically, knockdown of BTK in AML cell lines impaired the synergistic effect of the two drugs. In vivo study showed similar results as those seen in vitro. Abivertinib in combination with venetoclax could significantly prolong the survival time and reduce the tumor burden of MV4‐11‐NSG mice compared with those of control and single‐agent groups. Our in vitro and in vivo studies have shown that the combination of abivertinib and venetoclax may benefit AML patients, especially in patients resistant to venetoclax or those that relapse. New clinical trials will be planned.
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Avitinib is also a novel BTK inhibitor.
“Avitinib is also a novel BTK inhibitor.161,162”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [162]
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DiNardo, C. D., Pratz, K., Pullarkat, V., Jonas, B. A., Arellano, M., Becker, P. S., Frankfurt, O., Konopleva, M., Wei, A. H., Kantarjian, H. M., et al. (2019) · Blood · doi:10.1182/blood-2018-08-868752 · Cited by 1,825 · see citing works
Caenepeel, S., Brown, S. P., Belmontes, B., Moody, G., Keegan, K. S., Chui, D., Whittington, D. A., Huang, X., Poppe, L., Cheng, A. C., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0387 · Cited by 432 · see citing works
Self-citationDinardo, C. D., Rausch, C. R., Benton, C. B., Kadia, T. M., Jain, N., Pemmaraju, N., Daver, N. G., Covert, W. M., Marx, K. R., Mace, M. L., et al. (2017) · American Journal of Hematology · doi:10.1002/ajh.25000 · Cited by 425 · see citing works
Ramsey, H. E., Fischer, M. A., Lee, T., Gorska, A. E., Arrate, M. P., Fuller, L., Boyd, K. L., Strickland, S. A., Sensintaffar, J., Hogdal, L. J., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0140 · Cited by 385 · see citing works
Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment
Chen, X., Glytsou, C., Zhou, H., Narang, S., Reyna, D. E., López, A., Sakellaropoulos, T., Gong, Y., Kloetgen, A., Yap, Y. S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0117 · Cited by 344 · see citing works
Lancet, J. E., Cortes, J. E., Hogge, D. E., Tallman, M. S., Kovacsovics, T. J., Damon, L. E., Komrokji, R. S., Solomon, S. R., Kolitz, J. E., Cooper, M. A., et al. (2014) · Blood · doi:10.1182/blood-2013-12-540971 · Cited by 339 · see citing works
Pan, R., Ruvolo, V., Mu, H., Leverson, J. D., Nichols, G., Reed, J. C., Konopleva, M., & Andreeff, M. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.11.003 · Cited by 300 · see citing works
Survival and cure of acute myeloid leukaemia in E ngland, 1971‐2006: a population–based study
Shah, A., Andersson, T., Rachet, B., et al. (2013) · British Journal of Haematology · doi:10.1111/bjh.12425 · Cited by 207 · see citing works
Venetoclax-based therapies for acute myeloid leukemia
Guerra, V. A., Dinardo, C. D., & Konopleva, M. Y. (2019) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2019.05.008 · Cited by 180 · see citing works
Cortes, J. E., Goldberg, S. L., Feldman, E. J., Rizzeri, D. A., Hogge, D. E., Larson, M., Pigneux, A., Recher, C., Schiller, G., Warzocha, K., et al. (2015) · Cancer · doi:10.1002/cncr.28974 · Cited by 175 · see citing works
Moujalled, D. M., Pomilio, G., Ghiurau, C., Ivey, A., Salmon, J. M., Rijal, S., MacRaild, S., Zhang, L., Teh, T., Tiong, I. S., et al. (2018) · Leukemia · doi:10.1038/s41375-018-0261-3 · Cited by 171 · see citing works
Chyla, B., Daver, N. G., Doyle, K. J., McKeegan, E. M., Huang, X., Ruvolo, V. R., Wang, Z., Chen, K., Souers, A. J., Leverson, J. D., et al. (2018) · American Journal of Hematology · doi:10.1002/ajh.25146 · Cited by 148 · see citing works
Self-citationCotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells
Rahmani, M., Nkwocha, J., Hawkins, E., Pei, X., Parker, R. E., Kmieciak, M., Leverson, J. D., Sampath, D., Ferreira‐Gonzalez, A., & Grant, S. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3024 · Cited by 147 · see citing works
Identification of Bruton’s tyrosine kinase as a therapeutic target in acute myeloid leukemia
Rushworth, S. A., Murray, M. Y., Zaitseva, L., Bowles, K. M., & MacEwan, D. J. (2013) · Blood · doi:10.1182/blood-2013-06-511154 · Cited by 116 · see citing works
Combined venetoclax and alvocidib in acute myeloid leukemia
Bogenberger, J. M., Whatcott, C. J., Hansen, N., Delman, D., Shi, C.-X., Kim, W., Haws, H., Soh, K. K., Lee, Y. S., Peterson, P. W., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.22284 · Cited by 96 · see citing works
Xu, X., Mao, L., Xu, W., Tang, W., Zhang, X., Xi, B., Xu, R., Fang, X., Liu, J., Fang, C., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0281 · Cited by 87 · see citing works
Self-citationNew Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise
Bohl, S., Bullinger, L., & Rücker, F. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081983 · Cited by 86 · see citing works
Ryan, C. E., Sahaf, B., Logan, A. C., O'Brien, S. M., Byrd, J. C., Hillmen, P., Brown, J. R., Dyer, M. J. S., Mato, A. R., Keating, M. J., et al. (2016) · Blood · doi:10.1182/blood-2016-06-715284 · Cited by 77 · see citing works
Jain, P., Keating, M. J., Wierda, W. G., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1948 · Cited by 56 · see citing works
Anstee, N., Bilardi, R., Ng, A. P., Xu, Z., Robati, M., Vandenberg, C., & Cory, S. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0209-1 · Cited by 43 · see citing works
New Treatment Options for Acute Myeloid Leukemia in 2019
Cerrano, M., & Itzykson, R. (2019) · Current Oncology Reports · doi:10.1007/s11912-019-0764-8 · Cited by 40 · see citing works
Wei, H., Wang, Y., Zhou, C., et al. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0566-8 · Cited by 37 · see citing works
Ibrutinib selectively targets FLT3-ITD in mutant FLT3-positive AML
Wu, H., Hu, C., Wang, A., Weisberg, E., Wang, W., Chen, C., Zhao, Z., Yu, K., Liu, J., Wu, J., et al. (2015) · Leukemia · doi:10.1038/leu.2015.175 · Cited by 36 · see citing works
Older Patients With Acute Myeloid Leukemia: Treatment Challenges and Future Directions.
Finn, L. E., Dalovisio, A. P., & Foran, J. M. (2017) · PubMed Central · Cited by 35 · see citing works
Venetoclax with decitabine or azacitidine for AML
Das, M. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30824-6 · Cited by 31 · see citing works
Targeted therapy with a selective BCL-2 inhibitor in older patients with acute myeloid leukemia
Campos, E. D. V., & Pinto, R. (2018) · Hematology Transfusion and Cell Therapy · doi:10.1016/j.htct.2018.09.001 · Cited by 31 · see citing works
Huang, S., Pan, J., Jin, J., Li, C.-Y., Li, X., Huang, J., Huang, X., Xiao, Y., Li, F., Yu, M., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.07.008 · Cited by 27 · see citing works
Self-citationKurtz, S. E., Eide, C. A., Kaempf, A. J., Mori, M., Tognon, C. E., Borate, U., Druker, B. J., & Tyner, J. W. (2018) · Leukemia · doi:10.1038/s41375-018-0225-7 · Cited by 22 · see citing works
Wang, H., Pan, R., Zhang, X., et al. (2020) · Thoracic Cancer · doi:10.1111/1759-7714.13302 · Cited by 16 · see citing works
Self-citationPromising efficacy of novel BTK inhibitor AC0010 in mantle cell lymphoma
Yan, X., Zhou, Y., Huang, S., Li, X., Yu, M., Huang, J., Wang, J., Ma, Z., Jin, J., Pan, J., et al. (2018) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-017-2570-8 · Cited by 12 · see citing works
Self-citationFuture therapeutic options for patients with Waldenström macroglobulinemia
Castillo, J. J., Hunter, Z. R., Yang, G., Argyropoulos, K. V., Palomba, M. L., & Treon, S. P. (2016) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2016.08.021 · Cited by 4 · see citing works
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
- Authors
- Huang, S., Li, C., Zhang, X., Pan, J., Li, F., Lv, Y., Huang, J., Ling, Q., Ye, W., Mao, S., Huang, X., & Jin, J.
- Affiliations
- First Affiliated Hospital Zhejiang University (CN)
- Corresponding author
- Jin, Jie
- ORCID
- Venue
- Molecular Oncology
- Publisher
- Wiley
- Published
- 2020-07-03
- Volume
- 14
- Issue
- 10
- Pages
- 2560-2573
- ISSN
- 1574-7891 (ISSN-L)
- 1878-0261
- PMC
- PMC7530784
- OpenAlex
- W3033975532
- Cited by
- 7
- References
- 31
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 1
- FWCI
- 0.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81470305‐H0812, 81820108004)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- venetoclax, acute myeloid leukemia, BTK inhibition, BCL-2 inhibition, drug synergy, venetoclax resistance, combination therapy, apoptosis, G0/G1 cell cycle arrest, caspase activation, relapsed AML
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Acrylamides, Animals, Antineoplastic Agents, Bone Marrow Cells, Cell Survival, Drug Synergism, Hematopoietic Stem Cells, Humans, Piperazines, Pyrimidines, Sulfonamides, Leukemia, Myeloid, Acute, Survival Analysis, Mice, SCID, Mice, Inbred NOD, Apoptosis, Disease Progression, Antigens, CD34, Bridged Bicyclo Compounds, Heterocyclic, Proto-Oncogene Proteins c-bcl-2, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Cell Proliferation
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