CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast Cells
In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express <i>KIT</i> D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. C...
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| Format: | Article |
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MDPI AG
2022-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/13/3070 |
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| author | Mathias Schneeweiss-Gleixner Yüksel Filik Gabriele Stefanzl Daniela Berger Irina Sadovnik Karin Bauer Dubravka Smiljkovic Gregor Eisenwort Nadine Witzeneder Georg Greiner Gregor Hoermann Ana-Iris Schiefer Juliana Schwaab Mohamad Jawhar Andreas Reiter Wolfgang R. Sperr Michel Arock Peter Valent Karoline V. Gleixner |
| author_facet | Mathias Schneeweiss-Gleixner Yüksel Filik Gabriele Stefanzl Daniela Berger Irina Sadovnik Karin Bauer Dubravka Smiljkovic Gregor Eisenwort Nadine Witzeneder Georg Greiner Gregor Hoermann Ana-Iris Schiefer Juliana Schwaab Mohamad Jawhar Andreas Reiter Wolfgang R. Sperr Michel Arock Peter Valent Karoline V. Gleixner |
| author_sort | Mathias Schneeweiss-Gleixner |
| collection | DOAJ |
| description | In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express <i>KIT</i> D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the <i>KIT</i> D816V<sup>+</sup> MC line HMC-1.2. The CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4/CDK6 inhibitors induce apoptosis in CD34+/CD38− stem cells in AdvSM. Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials. |
| first_indexed | 2024-03-09T22:04:29Z |
| format | Article |
| id | doaj.art-6434804f1c8c454a99eeca4ea6cf9e93 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T22:04:29Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6434804f1c8c454a99eeca4ea6cf9e932023-11-23T19:43:54ZengMDPI AGCancers2072-66942022-06-011413307010.3390/cancers14133070CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast CellsMathias Schneeweiss-Gleixner0Yüksel Filik1Gabriele Stefanzl2Daniela Berger3Irina Sadovnik4Karin Bauer5Dubravka Smiljkovic6Gregor Eisenwort7Nadine Witzeneder8Georg Greiner9Gregor Hoermann10Ana-Iris Schiefer11Juliana Schwaab12Mohamad Jawhar13Andreas Reiter14Wolfgang R. Sperr15Michel Arock16Peter Valent17Karoline V. Gleixner18Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Pathology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Hematology and Oncology, University Medical Center Mannheim and Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, GermanyDepartment of Hematology and Oncology, University Medical Center Mannheim and Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, GermanyDepartment of Hematology and Oncology, University Medical Center Mannheim and Medical Faculty Mannheim, Heidelberg University, 69120 Heidelberg, GermanyLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaDepartment of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), 75013 Paris, FranceLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaLudwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, AustriaIn most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express <i>KIT</i> D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the <i>KIT</i> D816V<sup>+</sup> MC line HMC-1.2. The CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4/CDK6 inhibitors induce apoptosis in CD34+/CD38− stem cells in AdvSM. Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials.https://www.mdpi.com/2072-6694/14/13/3070systemic mastocytosis<i>KIT</i> D816VmidostaurinavapritinibCDK4/CDK6palbociclib |
| spellingShingle | Mathias Schneeweiss-Gleixner Yüksel Filik Gabriele Stefanzl Daniela Berger Irina Sadovnik Karin Bauer Dubravka Smiljkovic Gregor Eisenwort Nadine Witzeneder Georg Greiner Gregor Hoermann Ana-Iris Schiefer Juliana Schwaab Mohamad Jawhar Andreas Reiter Wolfgang R. Sperr Michel Arock Peter Valent Karoline V. Gleixner CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast Cells Cancers systemic mastocytosis <i>KIT</i> D816V midostaurin avapritinib CDK4/CDK6 palbociclib |
| title | CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast Cells |
| title_full | CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast Cells |
| title_fullStr | CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast Cells |
| title_full_unstemmed | CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast Cells |
| title_short | CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition in <i>KIT</i> D816V<sup>+</sup> Neoplastic Mast Cells |
| title_sort | cdk4 cdk6 inhibitors synergize with midostaurin avapritinib and nintedanib in inducing growth inhibition in i kit i d816v sup sup neoplastic mast cells |
| topic | systemic mastocytosis <i>KIT</i> D816V midostaurin avapritinib CDK4/CDK6 palbociclib |
| url | https://www.mdpi.com/2072-6694/14/13/3070 |
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