dc.contributor.advisor | Koch, Raphael PD Dr. | |
dc.contributor.author | Ksionsko, Nora Anna Maria | |
dc.date.accessioned | 2024-08-20T15:37:53Z | |
dc.date.available | 2024-08-27T00:50:07Z | |
dc.date.issued | 2024-08-20 | |
dc.identifier.uri | http://resolver.sub.uni-goettingen.de/purl?ediss-11858/15435 | |
dc.identifier.uri | http://dx.doi.org/10.53846/goediss-10686 | |
dc.format.extent | 127 | de |
dc.language.iso | eng | de |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject.ddc | 570 | de |
dc.title | Mechanistic Characterization of CDK9 Inhibition in T-Cell Lymphoma | de |
dc.type | doctoralThesis | de |
dc.contributor.referee | Koch, Raphael PD Dr. | |
dc.date.examination | 2024-05-23 | de |
dc.description.abstracteng | Mature T-cell lymphomas (mTCL) comprise a rare group of lymphoid malignancies with
very diverse genetical, clinical, and pathological characteristics that are in many cases
associated with poor prognosis. Current therapy options for mTCL are limited and result in
unsatisfying outcomes with high relapse rates, leaving a need for innovative treatment
regimens. In recent years, transient CDK9 inhibition (CDK9i) has emerged as a promising
approach to target transcriptionally addicted cancers, including aggressive lymphoma. To
evaluate the potential of CDK9i in mTCL, clinical grade inhibitors were tested on a panel of
genetically and transcriptionally characterized cell lines. Treatment resulted in a subtype
specific, heterogeneous pattern of sensitivity and resistance. While CDK9i sensitivity is
associated with the ALCL subtype and high MCL1 dependence/gene expression, resistance
is correlated with the CTCL subtype, high GATA3 expression and functional BCL-xL
dependence. Addressing cellular escape mechanisms to pharmacological CDK9i,
transcriptomic profiling and immunoblotting after short-term CDK9i revealed increased
activation of AKT signaling as a potential resistance mechanism. This finding was further
supported by a decreased sensitivity towards CDK9i upon introduction of a mysristoylated
and thus constitutively activated AKT in cell line models. Vice versa, inhibition of the
PI3K/AKT pathway with clinical grade PI3K inhibitors sufficiently suppressed AKT
phosphorylation upon CDK9i. In an in-vitro combinational screening, dual inhibition of
CDK9 and PI3K induced synergistic effects in multiple mTCL cell lines. Furthermore, this
combinational approach displayed enhanced cytotoxic effects in an ex-vivo treatment of
patient derived xenograft cells, providing a rationale for further in-vivo experiments and
clinical testing. Lastly, the phenomenon of acquired resistance was investigated through the
establishment of AZD4573 resistant (AZD4573res) clones from an initially sensitive cell line.
On a genetic level, AZD4573res clones acquired a frame-shift mutation in the tumor
suppressor gene LATS2. Further characterization of the acquired resistance on a functional
level through transcriptional profiling identified downregulation of p53 signaling and cell
death pathways in AZD4573res cells. Consistently, functional apoptosis profiling through
dynamic BH3 profiling after short-term CDK9i revealed diminished apoptotic priming, in
association with decreased expression of the pro-apoptotic effector protein BAK, indicating
decreased susceptibility to pro-apoptotic stimuli in AZD4573res cell lines. | de |
dc.contributor.coReferee | Dobbelstein, Matthias Prof. Dr. | |
dc.subject.eng | CDK9 | de |
dc.subject.eng | T-Cell Lymphoma | de |
dc.identifier.urn | urn:nbn:de:gbv:7-ediss-15435-8 | |
dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
dc.subject.gokfull | Biologie (PPN619462639) | de |
dc.description.embargoed | 2024-08-27 | de |
dc.identifier.ppn | 1899345213 | |
dc.notes.confirmationsent | Confirmation sent 2024-08-20T19:45:01 | de |