Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells
Abstract Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of white blood cells. Tyrosine kinase inhibitors (TKIs) are the standard treatment; however, resistance to BCR::ABL1 mutations remains challenging. WEE1, a checkpoint k...
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| Format: | Article |
| Language: | English |
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Springer
2025-07-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-03036-7 |
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| author | Seiichi Okabe Mitsuru Moriyama Akihiko Gotoh Daigo Akahane |
| author_facet | Seiichi Okabe Mitsuru Moriyama Akihiko Gotoh Daigo Akahane |
| author_sort | Seiichi Okabe |
| collection | DOAJ |
| description | Abstract Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of white blood cells. Tyrosine kinase inhibitors (TKIs) are the standard treatment; however, resistance to BCR::ABL1 mutations remains challenging. WEE1, a checkpoint kinase involved in mitosis and DNA repair, is a potential therapeutic target for CML treatment. Methods Ponatinib-resistant CML cells were screened to identify candidates for overcoming drug resistance. The efficacy of the ABL TKI asciminib and the WEE1 inhibitor MK-1775 was evaluated using proliferation and colony formation assays. Public database analysis (GSE100026) assessed WEE1/PKMYT1 expression in CML. Results In vitro screening identified MK-1775 as a promising therapeutic candidate. WEE1/PKMYT1 expression was elevated in CML cells compared to healthy cells. Both asciminib and MK-1775 inhibited CML cell proliferation after 72 h, with enhanced cytotoxicity when combined. Co-treatment reduced colony formation and induced G2/M arrest, whereas an increase in the sub-G1 cell population indicated apoptosis. Furthermore, the combination treatment disrupted the mitochondrial membrane potential. Conclusions The combination of asciminib and WEE1 inhibition demonstrated greater efficacy than either drug alone, suggesting a novel therapeutic strategy for treating CML. These findings provide insights into overcoming TKI resistance and highlight a promising approach for future clinical applications. |
| format | Article |
| id | doaj-art-06db1213b73b4e588ef844aee6c03a60 |
| institution | DOAJ |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-06db1213b73b4e588ef844aee6c03a602025-08-20T03:05:05ZengSpringerDiscover Oncology2730-60112025-07-0116111610.1007/s12672-025-03036-7Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cellsSeiichi Okabe0Mitsuru Moriyama1Akihiko Gotoh2Daigo Akahane3Department of Hematology, Tokyo Medical UniversityDepartment of Hematology, Tokyo Medical UniversityDepartment of Hematology, Tokyo Medical UniversityDepartment of Hematology, Tokyo Medical UniversityAbstract Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of white blood cells. Tyrosine kinase inhibitors (TKIs) are the standard treatment; however, resistance to BCR::ABL1 mutations remains challenging. WEE1, a checkpoint kinase involved in mitosis and DNA repair, is a potential therapeutic target for CML treatment. Methods Ponatinib-resistant CML cells were screened to identify candidates for overcoming drug resistance. The efficacy of the ABL TKI asciminib and the WEE1 inhibitor MK-1775 was evaluated using proliferation and colony formation assays. Public database analysis (GSE100026) assessed WEE1/PKMYT1 expression in CML. Results In vitro screening identified MK-1775 as a promising therapeutic candidate. WEE1/PKMYT1 expression was elevated in CML cells compared to healthy cells. Both asciminib and MK-1775 inhibited CML cell proliferation after 72 h, with enhanced cytotoxicity when combined. Co-treatment reduced colony formation and induced G2/M arrest, whereas an increase in the sub-G1 cell population indicated apoptosis. Furthermore, the combination treatment disrupted the mitochondrial membrane potential. Conclusions The combination of asciminib and WEE1 inhibition demonstrated greater efficacy than either drug alone, suggesting a novel therapeutic strategy for treating CML. These findings provide insights into overcoming TKI resistance and highlight a promising approach for future clinical applications.https://doi.org/10.1007/s12672-025-03036-7Chronic myeloid leukemiaABL inhibitor resistanceSTAMP inhibitorWEE1 inhibitor |
| spellingShingle | Seiichi Okabe Mitsuru Moriyama Akihiko Gotoh Daigo Akahane Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells Discover Oncology Chronic myeloid leukemia ABL inhibitor resistance STAMP inhibitor WEE1 inhibitor |
| title | Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells |
| title_full | Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells |
| title_fullStr | Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells |
| title_full_unstemmed | Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells |
| title_short | Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells |
| title_sort | targeting wee1 and asciminib suppresses abl tyrosine kinase inhibitor resistant chronic myeloid leukemia cells |
| topic | Chronic myeloid leukemia ABL inhibitor resistance STAMP inhibitor WEE1 inhibitor |
| url | https://doi.org/10.1007/s12672-025-03036-7 |
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