Identification and characterization of kinase-sparing aurora kinase A ligands for treatment of TP53-altered liver carcinomas

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Dokumentart: PhDThesis
Date: 2024-04-07
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Pharmazie
Advisor: Laufer, Stefan (Prof. Dr.)
Day of Oral Examination: 2022-04-07
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
610 - Medicine and health
Other Keywords: Leberkrebs
Aurora Kinase A
Aurora Kinase A
Cancer Therapy
Conformational Change
Liver Cancer
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Hepatocellular carcinoma (HCC) represents a major and increasing health problem, however, the therapy options for advanced stage HCC are very limited. Recent studies highlight the use of conformation changing AURKA inhibitors, like MLN8237, as novel treatment option of TP53-altered HCC. However, all existing AURKA inhibitors potently affect its kinase function, resulting in dose-limiting toxicities as shown in several clinical trials. To reduce such toxicities and thus enable the development of drugs with higher therapeutic index, we developed first-of-its kind kinase-spearing AURKA-ligands which specifically modulate the AURKA conformation and interactome. Specifically, using genetically defined murine HCC cell lines, I showed that the newly developed AURKA-ligands specifically kill Trp53-altered HCC cells with IC50 values in the low nanomolar range. This effect was independent of kinase inhibition, since neither the catalytic function of AURKA is reduced, nor that of any other of 320 tested wildtype kinases. In contrast to the clinically developed AURKA inhibitor MLN8237, neither non-tumorous cells nor liver cancer cells with TP53 wildtype status were affected by treatment with Aurora-ligands, thus underlining their unprecedented therapeutic index. Mechanistic analyses revealed, that the AURKA-ligands tethered the AURKA/TPX2 complex, thereby stabilizing both proteins resulting in an increase in AURKA activation. This robustly disturbed the mitotic spindle dynamics, leading to a continuous spindle assembly checkpoint activation, M phase arrest, mitotic defects and ultimately to cell death by mitotic catastrophe. I could prove that also TP53-altered human HCC cell lines are sensitive towards AURKA-ligands and that they also show abnormal spindle formation upon treatment. Further, by probing a comprehensive panel of lung cancer cell lines I showed that RB1 mutations in addition to TP53 mutations further sensitize for AURKA-ligands.

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