Abstract 4283: PLK4 inhibition: A therapeutic strategy to treat patients with TRIM37 amplified tumors

• Published in: Cancer research (Chicago, Ill.) Vol. 85; no. 8_Supplement_1; p. 4283
• Main Authors: Wong, Kristen, Menon, Debashish U., Zhang, Weichao, Wilson, Boris, Spletstoser, Jared
• Format: Journal Article
• Language: English
• Published: 21.04.2025
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2025-4283

TRIM37 is a breast cancer oncogene and crucial regulator of pericentriolar matrix (PCM) components. Tumors with amplified TRIM37, an E3-ubiquitin ligase, undergo mitotic catastrophe when Polo-like kinase 4 (PLK4) is inhibited. PLK4 is essential for centriole duplication, a key process in cell division. While several PLK4 kinase inhibitors have been identified, their selectivity and in vivo pharmacokinetic properties are suboptimal. In this study, cellular proliferation and pharmacodynamic assays were developed to optimize the activity and selectivity of PLK4 inhibitors. PLK4 inhibition more effectively inhibited cell proliferation in TRIM37-amplified breast and neuroblastoma cell lines. Conversely, TRIM37 knockout breast cancer cells showed reduced sensitivity to PLK4 inhibition. Mechanistically, PLK4 stability is controlled by its auto-phosphorylation, which triggers rapid degradation via the proteasomal pathway. Tool compounds confirmed that inhibition of PLK4 leads to its stabilization, establishing PLK4 stabilization as a pharmacodynamic biomarker for PLK4 inhibition. These assays will enable evaluation of PLK4 inhibitor activity and selectivity in TRIM37 amplified cells.