CCL5 mediates target-kinase independent resistance to FLT3 inhibitors in FLT3-ITD-positive AML.

Silvia Waldeck, Michael Rassner, Philip Keye, Marie Follo, Dieter Herchenbach, Cornelia Endres, Anne Charlet, Geoffroy Andrieux, Ulrich Salzer, Melanie Boerries, Justus Duyster, Nikolas von Bubnoff

Molecular oncology 2020 Apr

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FLT3-ITD tyrosine kinase inhibitors (TKI) show limited clinical activity in acute myeloid leukemia (AML) due to emerging resistance. TKI resistance is mediated by secondary FLT3-ITD mutations only in a minority of cases. We hypothesize that the cytokine CCL5 protects AML cells from TKI-mediated cell death and contributes to treatment resistance. We generated PKC412- and sorafenib-resistant MOLM-13 cell lines as an in vitro model to study TKI resistance in AML. Increased CCL5 levels were detected in supernatants from PKC412-resistant cell lines compared to TKI-sensitive cells. Moreover, CCL5 treatment of TKI-sensitive cells induced resistance to PKC412. In resistant cell lines with high CCL5 release, we observed a significant downregulation of the CCL5-receptor CCR5 and CXCR4. In these cell lines, TKI resistance could be partly overcome by addition of the CXCR4-receptor antagonist plerixafor. Microarray and intracellular flow cytometry analyses revealed increased p-Akt or p-Stat5 levels in PKC412-resistant cell lines releasing high amounts of CCL5. Treatment with the CXCR4 antagonist plerixafor, αCCL5, or CCR5-targeting siRNA led to a decrease of p-Akt-positive cells. Transient transfection of sensitive MOLM-13 cells with a CCL5-encoding vector mediated resistance against PKC412 and led to an increase in p-Akt-positive and p-Stat5-positive cells. Isolated AML blasts from patients treated with PKC412 revealed that CCL5 transcript levels increase significantly at relapse. Taken together, our findings indicate that CCL5 mediates resistance to FLT3-TKIs in FLT3-ITD-mutated AML and could possibly serve as a biomarker to predict drug resistance. © 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Citation

Silvia Waldeck, Michael Rassner, Philip Keye, Marie Follo, Dieter Herchenbach, Cornelia Endres, Anne Charlet, Geoffroy Andrieux, Ulrich Salzer, Melanie Boerries, Justus Duyster, Nikolas von Bubnoff. CCL5 mediates target-kinase independent resistance to FLT3 inhibitors in FLT3-ITD-positive AML. Molecular oncology. 2020 Apr;14(4):779-794