Uncovering actionable signaling pathways required for solid tumor brain metastasis

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ABSTRACT Despite the emergence of targeted therapies and immune checkpoint inhibitors for the treatment of diverse solid tumor types, the metastatic spread of tumor cells to distant organ sites remains the primary determinant of cancer-related mortality. As patient survival increases owing to improved management of primary tumor burden, of particular concern is the rising incidence of brain metastases which with few exceptions reduce patient survival to the order of weeks or months. Metastases to the brain are most commonly seen in patients with tumors of the lung, breast, and melanoma. Therapies targeting “driver” mutations and gene amplifications such as EGFR (lung), HER2 (breast), and RAF/MEK (melanoma) have been ineffective at treating brain metastases owing to transient responses and lack of blood-brain barrier penetrance. The use of checkpoint inhibitors for the management of brain metastases has also been met with limited clinical success. As it stands, no effective therapies exist for patients suffering from brain metastases, therefore the discovery of novel strategies by which to treat metastatic disease within the brain is an urgent clinical need. This proposal describes our ongoing work to characterize a novel AXL-ABL2-TAZ signaling axis in brain-metastatic lung cancer cells through the implementation of in vivo mouse models of brain metastasis combined with follow-up mechanistic studies. We find that activation of this signaling axis drives expression of brain metastasis-associated genes which allow disseminated tumor cells to adapt and survive in the brain microenvironment. Importantly, targeted inhibition of AXL or the ABL kinases impairs brain-metastatic outgrowth and significantly extends survival in brain metastasis- bearing mice. Lastly, I describe future studies to be conducted as a postdoctoral candidate by combining my current expertise in cell signaling and the use of in vivo mouse models with high-throughput functional genomics platforms to unbiasedly identify the molecular mediators governing solid tumor metastasis to the brain.