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Significance Among all cancer types, lung cancer patients exhibit the highest prevalence of brain metastasis, often associated with cognitive impairment, seizures, decline in quality of life, and decreased survival. Limited therapeutic options are currently available to treat brain metastasis. A comprehensive understanding of the signaling pathways and transcriptional networks required for survival and growth of brain-metastatic cancer cells is needed to develop effective strategies to treat this disease. Here, we report that the Heat Shock Transcription Factor 1 (HSF1) is upregulated in brain-metastatic lung cancer cells and is required for brain metastasis in mice. Importantly, we show that the HSF1-dependent expression of E2F target genes implicated in cell cycle progression and survival is decreased by blood–brain barrier-penetrant ABL allosteric inhibitors.

The ABL2 kinase regulates an HSF1-dependent transcriptional program required for lung adenocarcinoma brain metastasis