Abstract LB-350: In vivo kinome screen reveals potential drivers of brain metastasis

Abstract

Abstract Brain metastasis remains an unmet medical need, as its incidence continues to rise while treatment options remain palliative. Advances in targeted therapy for breast cancer have prolonged patient survival through better control of the systemic disease, but an ever-increasing number of patients later recur with brain metastasis. As no effective therapies exist for brain metastasis, the median survival of patients is less than one year. To tackle this growing clinical challenge, we sought to better understand the biological mechanism of brain metastasis and to identify novel targets for intervention. We chose to focus on kinases, as they both occupy the central nodes of cancer cell signaling pathways and structurally lend themselves to targeting by small molecules. To identify novel therapeutic targets, we performed an unbiased kinome screen in vivo for determination of brain metastasis driver kinases. We injected MDA-MB-231 human breast cancer cells overexpressing pools of 16-20 kinase ORFs into the carotid artery of nude mice to form experimental brain metastasis. Several of the kinase pools led to decreased brain metastasis-specific survival, decreasing survival time by as much as 50% relative to controls. We then performed targeted next-generation sequencing (NGS) of the pre-and post-injection tumor cells to determine those kinases most enriched in vivo, revealing 31 ORFs that were significantly increased in vivo in multiple animals. To validate the clinical relevance of these potential targets, we examined their expression in a collection of 32 human brain metastases by RNA-seq, and observed that the majority of the ORFs (29/31) were indeed expressed. One of the kinases with the highest in vivo enrichment and expression in human brain metastases was hexokinase 2 (HK2), an important glycolysis regulator that has been previously implicated in brain metastasis and served to validate our findings. Several other candidate kinases were also related to glycolysis and other metabolic pathways, suggesting that these kinases enable metastatic cancer cells to survive in the nutrient-restricted brain environment. Functional validation of these newly identified kinases as true drivers of brain metastasis will reveal whether they have potential to serve as the first targets of brain metastasis-targeted therapy. Citation Format: Frank J. Lowery, Sunil Acharya, Yong Xia, Chenyu Zhang, Jodi M. Saunus, Dihua Yu. In vivo kinome screen reveals potential drivers of brain metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-350.