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Zielgerichtete Therapien beim Mantelzelllymphom. Der neue CDK4/6-Inhibitor Abemaciclib in Mono- und Kombinationstherapie
Zielgerichtete Therapien beim Mantelzelllymphom. Der neue CDK4/6-Inhibitor Abemaciclib in Mono- und Kombinationstherapie
Mantle cell lymphoma is characterized by the t(11;14)(q13;q32) translocation juxtaposing the CCND1 gene locus to the Ig heavy chain locus, resulting in a cyclin D1 overexpression. Cyclin D1 forms a complex with CDK4 and 6 and deactivates Rb through phosphorylation, leading to cell cycle progression from G1- into S-phase. Abemaciclib is a novel potent small molecule CDK4/6 inhibitor and therefore poses a rational approach in MCL therapy. In this study we evaluated the effect of abemaciclib as a single agent and in combination therapy with inhibitors of the BCR pathway or cytarabine in MCL and DLBCL cells. We demonstrate, that abemaciclib as a single agent leads to potent growth inhibition in low nanomolar doses through a strong, nontoxic and reversible G1-arrest in three of four MCL cells, whereas the effect on DLBCL cells is less distinct. The G1-arrest is induced by dephosphorylation of Rb in all cell lines with mostly unaffected expression levels of CDK4 or cyclin D1. However, we further show that abemaciclib leads to dephosphorylation of Akt on position Ser473 and Thr308 in sensitive but not in resistant MCL cell lines, imposing a possible role for Akt as a biomarker for abemaciclib resistance. With the abemaciclib effect being largely nontoxic and reversible, combination with other therapeutic agents is important. Here we show, that especially the sequential combination of an abemaciclib induced G1-arrest followed by ibrutinib or cytarabine poses great potential for synergism but also carries a considerable risk of antagonistic interactions. While ibrutinib acts synergistically when administered in G1-arrest, a lasting G1-arrest protects MCL cells from cytotoxic treatment by cytarabine. However, by exploiting the reversible effect of abemaciclib, MCL cells can be released from G1-arrest through inhibitor washout. This leads to a synchronized S-phase entry and sensitization to cytarabine treatment. Therefore, rational drug combinations may achieve major benefits, if possible adverse interactions are considered and studied carefully prior to testing. Further studies need to address the interactions with other targeted approaches of the B-cell receptor pathway to better understand the underlying molecular mechanisms.
Mantle Cell Lymphoma, Abemaciclib, Cell cycle, CDK4/6, Combination therapy
Fischer, Luca
2019
German
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Fischer, Luca (2019): Zielgerichtete Therapien beim Mantelzelllymphom: Der neue CDK4/6-Inhibitor Abemaciclib in Mono- und Kombinationstherapie. Dissertation, LMU München: Faculty of Medicine
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Abstract

Mantle cell lymphoma is characterized by the t(11;14)(q13;q32) translocation juxtaposing the CCND1 gene locus to the Ig heavy chain locus, resulting in a cyclin D1 overexpression. Cyclin D1 forms a complex with CDK4 and 6 and deactivates Rb through phosphorylation, leading to cell cycle progression from G1- into S-phase. Abemaciclib is a novel potent small molecule CDK4/6 inhibitor and therefore poses a rational approach in MCL therapy. In this study we evaluated the effect of abemaciclib as a single agent and in combination therapy with inhibitors of the BCR pathway or cytarabine in MCL and DLBCL cells. We demonstrate, that abemaciclib as a single agent leads to potent growth inhibition in low nanomolar doses through a strong, nontoxic and reversible G1-arrest in three of four MCL cells, whereas the effect on DLBCL cells is less distinct. The G1-arrest is induced by dephosphorylation of Rb in all cell lines with mostly unaffected expression levels of CDK4 or cyclin D1. However, we further show that abemaciclib leads to dephosphorylation of Akt on position Ser473 and Thr308 in sensitive but not in resistant MCL cell lines, imposing a possible role for Akt as a biomarker for abemaciclib resistance. With the abemaciclib effect being largely nontoxic and reversible, combination with other therapeutic agents is important. Here we show, that especially the sequential combination of an abemaciclib induced G1-arrest followed by ibrutinib or cytarabine poses great potential for synergism but also carries a considerable risk of antagonistic interactions. While ibrutinib acts synergistically when administered in G1-arrest, a lasting G1-arrest protects MCL cells from cytotoxic treatment by cytarabine. However, by exploiting the reversible effect of abemaciclib, MCL cells can be released from G1-arrest through inhibitor washout. This leads to a synchronized S-phase entry and sensitization to cytarabine treatment. Therefore, rational drug combinations may achieve major benefits, if possible adverse interactions are considered and studied carefully prior to testing. Further studies need to address the interactions with other targeted approaches of the B-cell receptor pathway to better understand the underlying molecular mechanisms.