ABL kinases promote lung cancer brain metastasis through regulation of transcriptional networks

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ABSTRACT Lung cancer has the highest prevalence of brain metastasis among all other cancer types, occurring in approximately 40% of patients. The presence of lung cancer brain metastases (LCBM) is associated with cognitive decline and a median survival of 4-6 months. Currently utilized therapies for treating LCBMs include whole brain radiation therapy (WBRT), chemotherapies, and targeted therapies aimed at kinases with “driver” mutations. The use of WBRT increases patient cognitive decline, while targeted therapies have been proven ineffective due to variable responses and the development of drug resistance. Thus, there is an obvious unmet clinical need to better understand the molecular mechanisms that promote LCBM and subsequently use these discoveries to develop new therapeutic strategies. Our laboratory discovered using an in vivo model of brain metastasis that Abelson tyrosine protein kinase 2 (ABL2) promotes LCBM by propagating a feed-forward loop consisting of ABL2, AXL receptor tyrosine kinase, and the TAZ transcriptional co-activator. Recently, my preliminary data revealed an ABL-dependent stabilization and transcriptional activation of hypoxia inducible factor-1α (HIF-1α) and heatshock factor 1 (HSF1) in this model. Activation of the HIF-1α and HSF1 transcription networks in cancer is associated with tumor proliferation, metastasis, and therapy resistance. Therefore, my central hypothesis is that the ABL kinases regulate multiple transcriptional networks that promote lung cancer brain metastasis and therapy resistance. I will examine this hypothesis through the following two aims: 1) Define the ABL-regulated HIF-1α transcription network required for lung cancer brain metastasis, and 2) Identify ABL- dependent HSF1- regulated pathways necessary for lung cancer colonization of the brain. These aims will evaluate whether increased expression of HIF-1α, HSF1, and TAZ can be used as biomarkers for lung cancer patients with brain metastasis and whether blood brain barrier permeable ABL kinase inhibitors might be an effective novel therapy for treating brain metastatic lung cancer.