Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance
Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of <i>BCR::ABL1</i> are the most extensively studied mechanism of TKI resistance...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/18/13806 |
| _version_ | 1797579702678847488 |
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| author | Ryo Yoshimaru Yosuke Minami |
| author_facet | Ryo Yoshimaru Yosuke Minami |
| author_sort | Ryo Yoshimaru |
| collection | DOAJ |
| description | Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of <i>BCR::ABL1</i> are the most extensively studied mechanism of TKI resistance in CML, but <i>BCR::ABL1</i>-independent mechanisms are involved in some cases. There are two known types of mechanisms that contribute to resistance: mutations in known cancer-related genes; and Philadelphia-associated rearrangements, a novel mechanism of genomic heterogeneity that occurs at the time of the Philadelphia chromosome formation. Most chronic-phase and accelerated-phase CML patients who were treated with the third-generation TKI for drug resistance harbored one or more cancer gene mutations. Cancer gene mutations and additional chromosomal abnormalities were found to be independently associated with progression-free survival. The novel agent asciminib specifically inhibits the ABL myristoyl pocket (STAMP) and shows better efficacy and less toxicity than other TKIs due to its high target specificity. In the future, pooled analyses of various studies should address whether additional genetic analyses could guide risk-adapted therapy and lead to a final cure for CML. |
| first_indexed | 2024-03-10T22:40:51Z |
| format | Article |
| id | doaj.art-02c8b4406c564b32bc0e47e0db664261 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T22:40:51Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-02c8b4406c564b32bc0e47e0db6642612023-11-19T11:03:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124181380610.3390/ijms241813806Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming ResistanceRyo Yoshimaru0Yosuke Minami1Department of Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi 277-8577, JapanDepartment of Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi 277-8577, JapanTyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of <i>BCR::ABL1</i> are the most extensively studied mechanism of TKI resistance in CML, but <i>BCR::ABL1</i>-independent mechanisms are involved in some cases. There are two known types of mechanisms that contribute to resistance: mutations in known cancer-related genes; and Philadelphia-associated rearrangements, a novel mechanism of genomic heterogeneity that occurs at the time of the Philadelphia chromosome formation. Most chronic-phase and accelerated-phase CML patients who were treated with the third-generation TKI for drug resistance harbored one or more cancer gene mutations. Cancer gene mutations and additional chromosomal abnormalities were found to be independently associated with progression-free survival. The novel agent asciminib specifically inhibits the ABL myristoyl pocket (STAMP) and shows better efficacy and less toxicity than other TKIs due to its high target specificity. In the future, pooled analyses of various studies should address whether additional genetic analyses could guide risk-adapted therapy and lead to a final cure for CML.https://www.mdpi.com/1422-0067/24/18/13806chronic myeloid leukemiagenome profilingasciminib |
| spellingShingle | Ryo Yoshimaru Yosuke Minami Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance International Journal of Molecular Sciences chronic myeloid leukemia genome profiling asciminib |
| title | Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance |
| title_full | Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance |
| title_fullStr | Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance |
| title_full_unstemmed | Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance |
| title_short | Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance |
| title_sort | genetic landscape of chronic myeloid leukemia and a novel targeted drug for overcoming resistance |
| topic | chronic myeloid leukemia genome profiling asciminib |
| url | https://www.mdpi.com/1422-0067/24/18/13806 |
| work_keys_str_mv | AT ryoyoshimaru geneticlandscapeofchronicmyeloidleukemiaandanoveltargeteddrugforovercomingresistance AT yosukeminami geneticlandscapeofchronicmyeloidleukemiaandanoveltargeteddrugforovercomingresistance |