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Combinaisons de nouveaux inhibiteurs de désacétylase d’histones 6 avec des inhibiteurs de tyrosine kinase pour le traitement de la leucémie myéloïde chronique

Abstract : Breakpoint cluster region-Abelson (BCR-ABL)+ chronic myeloid leukemia (CML) patients receive tyrosine kinase inhibitors (TKIs) such as imatinib as the first-line treatment; however, some patients develop resistances and severe adverse effects. Combination treatments, especially with histone deacetylase (HDAC)6 inhibitors (HDAC6i), appear as an attractive option to prevent TKI resistances considering the capacity of HDAC6i to downregulate BCR-ABL. Moreover, HDAC6 is implicated in protein degradation pathways, so that its inhibition combined with that of the proteasome could sensitize cells to TKIs. Thus, we hypothesized that HDAC6i combined to TKIs could be effective for CML treatment. In the first part, we compared the anti-CML effects of a HDAC6i identified in our laboratory, compound 7b, to the reference HDAC6i tubacin, in combination with imatinib. Results showed that the imatinib-7b combination generated stronger anti- CML effects than imatinib-tubacin. Especially, the imatinib-7b combination elicited a potent synergistic caspase- dependent apoptotic cell death and drastically reduced the proportion of cancer stem cells in K562 CML cells, whereas it only moderately impacted various healthy cell models. Ultimately, the imatinib-7b combination decreased more potently the colony forming capacities and tumor mass formation of CML cells in a semisolid methylcellulose medium and in xenografted zebrafishes, respectively, compared to each compound alone. Mechanistically, the combination induced BCR-ABL ubiquitination and downregulation leading to a dysregulation of multiple key proteins of its downstream pathways involved in CML proliferation and survival. Results tend to demonstrate that 7b could target the second site. In the second part, we initiated a study of a novel hydroxamate-based HDAC6i, MAKV-15, and preliminary results demonstrated it triggered BCR-ABL downregulation. Accordingly, in pre-treatment with bortezomib it sensitizes CML cells to imatinib leading to enhanced caspase-dependent apoptotic death in imatinib-sensitive and imatinib-resistant CML cells. Considering that HDAC6 is reported to possess two functional catalytic sites, we finally attempted to determine which catalytic site is targeted by these HDAC6i. Taken together, our results suggest that HDAC6i potentiate the effect of imatinib and could overcome TKI resistance in CML cells and therefore such combination may represent a promising therapeutic approach for CML patients.
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https://hal.univ-lorraine.fr/tel-02555739
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Hélène Losson. Combinaisons de nouveaux inhibiteurs de désacétylase d’histones 6 avec des inhibiteurs de tyrosine kinase pour le traitement de la leucémie myéloïde chronique. Biochimie, Biologie Moléculaire. Université de Lorraine, 2020. Français. ⟨NNT : 2020LORR0003⟩. ⟨tel-02555739⟩

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