Abstract 4478: Development and characterization of kinase sparing TPX2-tethering Aurora kinase A ligands for cancer therapy

Abstract

Abstract A major limitation in the treatment of cancer is the limited therapeutic index of currently available chemotherapies or molecularly targeted therapies. Drug related toxicities often necessitate restricted drug dosing regimens, resulting in subtotal tumor remissions, which represent an important cause for tumor recurrences and the development of therapy resistance. Following up on previous work suggesting Aurora kinase A (AURKA) as a promising therapeutic target for the treatment of TP53 altered liver carcinomas (Dauch D. et al., Nat. Med., 2016) and TP53; RB1 altered small cell lung carcinomas (Gong X. et al., Cancer Discovery, 2019), we here report on the development and characterization of first in class kinase sparing AURKA ligands, which selectively kill TP53 deficient liver cancer cells and TP53; RB1 deficient small cell lung cancer cells by tethering AURKA to its binding partner TPX2 in mitotic cells. Small molecule mediated stabilization of AURKA/TPX2 complexes resulted in formation of multipolar spindles and subsequent cell death through mitotic catastrophe. Mechanistically, we were able to show that the hypersensitivity of TP53 deficient liver cancer cells and TP53; Rb1 deficient small cell lung cancer cells towards AURKA ligands is due to low expression levels of the antiapoptotic protein MCL1, which is necessary for survival of cancer cells in prolonged mitosis. Our novel AURKA ligands do not affect the kinase function of AURKA and thus, in contrast to conventional AURKA kinase inhibitors, can be administered continuously to mice without inducing toxicity related to inhibition of kinase related non-canonical (non-mitotic) functions of AURKA in normal cells or TP53 and RB1 wildtype cancer cells. Preclinical therapy studies in cell-line derived xenograft (CDX) tumor models of small cell lung cancer (SCLC) and orthotopic models of TP53 altered hepatocellular carcinoma and TP53;Rb1 altered SCLC demonstrated marked monotherapeutic efficacy of AURKA ligands. Conceptually, our herein provided data suggest that small molecules designed to stabilize protein-protein interactions represent powerful anti-cancer drugs with exceptional therapeutic window and thus open a venue towards the development of novel cancer therapies. Citation Format: Athina Anastasia Moschopoulou, Melanie Henning, Benedikt Wagner, Dirk Flötgen, Juliander Reiner, Yulia Skliarenko, Stefan Zwirner, Clemens Hinterleitner, Marco Seehawer, Luana dArtista, Elke Rist, Tatu Pantsar, Thales Kronenberger, Daniel Dauch, Corinna Gehring-Khav, Antti Poso, Liudmila Andreeva, Matthias Schwab, Michael Forster, Wolfgang Albrecht, Stefan Laufer, Lars Zender. Development and characterization of kinase sparing TPX2-tethering Aurora kinase A ligands for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4478.