Abstract 5571: Identifying and targeting novel kinase regulators for cancer metastasis

Abstract Background: Metastasis is responsible for >90% of cancer death. However, metastasis is still poorly understood and the current approaches to prevent or treat human metastatic cancers are largely unsuccessful. Methods and Results: Through RNAi and cDNA functional screening, genomics analysis, and functional validations, we have identified several critical but previously unknown/understudied kinase regulators for metastasis. As an example, shRNA screening revealed that GPCR-kinase 3 (GRK3) is essential preferentially for highly metastatic cancer cells as compared to lowly metastatic cancer cells. GRK3 is significantly overexpressed in metastatic prostate tumors from patients, especially in the aggressive variant of prostate cancers, so called treatment-related neuroendocrine prostate cancer (NEPC). We further found that GRK3 is a key missing link between two prominent phenotypes of NEPC, i.e. angiogenesis and neuroendocrine feature. Mechanistically, GRK3 phosphorylates histone deacetylase 2 (HDAC2) at S394 and enhances HDAC2’s epigenetic activity. Through compound library screening, we have identified several compounds that block the kinase activity of GRK3 much more potently than that of GRK2, the closest-related kinase to GRK3. Of note, our GRK3 inhibitors could significantly inhibit NEPC cell growth in culture and in mouse xenografts. Another group of potential metastasis regulators we identified are new EMT-regulating kinases from our kinome cDNA screening for epithelial-mesenchymal transition (EMT). For example, mixed lineage kinase ZAK positively regulates EMT phenotypes and migration of cancer cells in culture, as well as metastasis in mice. ZAK overexpression correlates with poor prognosis in cancer patients. We are carrying out in silicon docking analysis and chemical genomics to identify potent and specific inhibitors for ZAK as research tools and drug candidates for metastatic cancers. Conclusions: Our robust and unbiased functional screening has identified several novel kinase regulators and potential drug targets for cancer metastasis. For example, GRK3 has emerged as a critical kinase for metastatic prostate cancer cells and a key regulator of aggressive neuroendocrine prostate cancer phenotypes, while ZAK has been identified as a potent new regulator of epithelial-to-mesenchymal transition (EMT). Citation Format: Wenliang Li. Identifying and targeting novel kinase regulators for cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5571.