Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells
Abstract Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo dem...
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Nature Portfolio
2021
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oai:doaj.org-article:dba1f40c656e42c3b03434ba4b5925512021-12-02T17:05:00ZEfficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells10.1038/s41598-021-85734-02045-2322https://doaj.org/article/dba1f40c656e42c3b03434ba4b5925512021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85734-0https://doaj.org/toc/2045-2322Abstract Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients’ response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.Marc G. BergerBenjamin LebecqueThomas TassinLouis-Thomas DannusJuliette BergerMélanie SoucalAgnès GuerciPascale Cony-MakhoulHyacinthe JohnsonGabriel EtienneDenis GuyotatMarie-Claude GagnieuBruno PereiraSandrine SauguesOlivier TournilhacEric HermetCéline BourgneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
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DOAJ |
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Medicine R Science Q |
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Medicine R Science Q Marc G. Berger Benjamin Lebecque Thomas Tassin Louis-Thomas Dannus Juliette Berger Mélanie Soucal Agnès Guerci Pascale Cony-Makhoul Hyacinthe Johnson Gabriel Etienne Denis Guyotat Marie-Claude Gagnieu Bruno Pereira Sandrine Saugues Olivier Tournilhac Eric Hermet Céline Bourgne Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells |
| description |
Abstract Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients’ response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response. |
| format |
article |
| author |
Marc G. Berger Benjamin Lebecque Thomas Tassin Louis-Thomas Dannus Juliette Berger Mélanie Soucal Agnès Guerci Pascale Cony-Makhoul Hyacinthe Johnson Gabriel Etienne Denis Guyotat Marie-Claude Gagnieu Bruno Pereira Sandrine Saugues Olivier Tournilhac Eric Hermet Céline Bourgne |
| author_facet |
Marc G. Berger Benjamin Lebecque Thomas Tassin Louis-Thomas Dannus Juliette Berger Mélanie Soucal Agnès Guerci Pascale Cony-Makhoul Hyacinthe Johnson Gabriel Etienne Denis Guyotat Marie-Claude Gagnieu Bruno Pereira Sandrine Saugues Olivier Tournilhac Eric Hermet Céline Bourgne |
| author_sort |
Marc G. Berger |
| title |
Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells |
| title_short |
Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells |
| title_full |
Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells |
| title_fullStr |
Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells |
| title_full_unstemmed |
Efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature CD34− and immature CD34+ cells |
| title_sort |
efficiency of nilotinib to target chronic phase-chronic myeloid leukaemia primary mature cd34− and immature cd34+ cells |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/dba1f40c656e42c3b03434ba4b592551 |
| work_keys_str_mv |
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| _version_ |
1718381820601434112 |