Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid Leukemia
Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring <i>FLT3</i>-ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeut...
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/24/6181 |
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| author | Javier Bregante Anna Schönbichler Daniel Pölöske Lina Degenfeld-Schonburg Garazi Monzó Contreras Emir Hadzijusufovic Elvin D. de Araujo Peter Valent Richard Moriggl Anna Orlova |
| author_facet | Javier Bregante Anna Schönbichler Daniel Pölöske Lina Degenfeld-Schonburg Garazi Monzó Contreras Emir Hadzijusufovic Elvin D. de Araujo Peter Valent Richard Moriggl Anna Orlova |
| author_sort | Javier Bregante |
| collection | DOAJ |
| description | Constitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring <i>FLT3</i>-ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeutic improvement. However, due to the emergence of resistance mechanisms, <i>FLT3</i>-ITD<sup>+</sup> AML remains a clinical challenge. We performed an unbiased drug screen to identify 18 compounds as particularly efficacious against <i>FLT3</i>-ITD<sup>+</sup> AML. Among these, we characterized two investigational compounds, WS6 and ispinesib, and two approved drugs, ponatinib and cabozantinib, in depth. We found that WS6, although not yet investigated in oncology, shows a similar mechanism and potency as ponatinib and cabozantinib. Interestingly, ispinesib and cabozantinib prevent activation of AXL, a key driver and mechanism of drug resistance in <i>FLT3</i>-ITD<sup>+</sup> AML patients. We further investigated synergies between the selected compounds and found that combination treatment with ispinesib and cabozantinib or ponatinib shows high synergy in <i>FLT3</i>-ITD<sup>+</sup> AML cell lines and patient samples. Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting <i>FLT3</i>-ITD<sup>+</sup> AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in <i>FLT3</i>-ITD<sup>+</sup> AML remains to be determined in clinical trials. |
| first_indexed | 2024-03-10T04:32:07Z |
| format | Article |
| id | doaj.art-c698b3152139495bbdb18d8460bee9b2 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:32:07Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-c698b3152139495bbdb18d8460bee9b22023-11-23T04:04:51ZengMDPI AGCancers2072-66942021-12-011324618110.3390/cancers13246181Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid LeukemiaJavier Bregante0Anna Schönbichler1Daniel Pölöske2Lina Degenfeld-Schonburg3Garazi Monzó Contreras4Emir Hadzijusufovic5Elvin D. de Araujo6Peter Valent7Richard Moriggl8Anna Orlova9Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, AustriaDepartment of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, AustriaDepartment of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON L5L1C6, CanadaDepartment of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, AustriaInstitute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, AustriaConstitutive activation of FLT3 by ITD mutations is one of the most common genetic aberrations in AML, present in ~1/3 of cases. Patients harboring <i>FLT3</i>-ITD display worse clinical outcomes. The integration and advancement of FLT3 TKI in AML treatment provided significant therapeutic improvement. However, due to the emergence of resistance mechanisms, <i>FLT3</i>-ITD<sup>+</sup> AML remains a clinical challenge. We performed an unbiased drug screen to identify 18 compounds as particularly efficacious against <i>FLT3</i>-ITD<sup>+</sup> AML. Among these, we characterized two investigational compounds, WS6 and ispinesib, and two approved drugs, ponatinib and cabozantinib, in depth. We found that WS6, although not yet investigated in oncology, shows a similar mechanism and potency as ponatinib and cabozantinib. Interestingly, ispinesib and cabozantinib prevent activation of AXL, a key driver and mechanism of drug resistance in <i>FLT3</i>-ITD<sup>+</sup> AML patients. We further investigated synergies between the selected compounds and found that combination treatment with ispinesib and cabozantinib or ponatinib shows high synergy in <i>FLT3</i>-ITD<sup>+</sup> AML cell lines and patient samples. Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting <i>FLT3</i>-ITD<sup>+</sup> AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in <i>FLT3</i>-ITD<sup>+</sup> AML remains to be determined in clinical trials.https://www.mdpi.com/2072-6694/13/24/6181acute myeloid leukemiatyrosine kinase inhibitorFMS-like tyrosine kinase 3targeted therapyponatinibcabozantinib |
| spellingShingle | Javier Bregante Anna Schönbichler Daniel Pölöske Lina Degenfeld-Schonburg Garazi Monzó Contreras Emir Hadzijusufovic Elvin D. de Araujo Peter Valent Richard Moriggl Anna Orlova Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid Leukemia Cancers acute myeloid leukemia tyrosine kinase inhibitor FMS-like tyrosine kinase 3 targeted therapy ponatinib cabozantinib |
| title | Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid Leukemia |
| title_full | Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid Leukemia |
| title_fullStr | Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid Leukemia |
| title_full_unstemmed | Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid Leukemia |
| title_short | Efficacy and Synergy of Small Molecule Inhibitors Targeting <i>FLT3</i>-ITD<sup>+</sup> Acute Myeloid Leukemia |
| title_sort | efficacy and synergy of small molecule inhibitors targeting i flt3 i itd sup sup acute myeloid leukemia |
| topic | acute myeloid leukemia tyrosine kinase inhibitor FMS-like tyrosine kinase 3 targeted therapy ponatinib cabozantinib |
| url | https://www.mdpi.com/2072-6694/13/24/6181 |
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