期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 52, 页码 33486-33495出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2007991117
关键词
brain metastasis; ABL2; HSF1; lung adenocarcinoma; ABL kinases
资金
- NIH National Cancer Institute [R01CA195549, F31CA22496001, F99CA24573201, F31CA2432-93-01A1, 5T32GM007105-44]
- Lung Cancer Research Foundation Free to Breathe Metastasis Research Grant
- Emerson Collective
- Duke SPORE in Brain Cancer Grant [P50CA190991]
Brain metastases are the most common intracranial tumors in adults and are associated with increased patient morbidity and mortality. Limited therapeutic options are currently available for the treatment of brain metastasis. Here, we report on the discovery of an actionable signaling pathway utilized by metastatic tumor cells whereby the transcriptional regulator Heat Shock Factor 1 (HSF1) drives a transcriptional program, divergent from its canonical role as the master regulator of the heat shock response, leading to enhanced expression of a subset of E2F transcription factor family gene targets. We find that HSF1 is required for survival and outgrowth by metastatic lung cancer cells in the brain parenchyma. Further, we identify the ABL2 tyrosine kinase as an upstream regulator of HSF1 protein expression and show that the Src-homology 3 (SH3) domain of ABL2 directly interacts with HSF1 protein at a noncanonical, proline-independent SH3 interaction motif. Pharmacologic inhibition of the ABL2 kinase using small molecule allosteric inhibitors, but not ATP-competitive inhibitors, disrupts this interaction. Importantly, knockdown as well as pharmacologic inhibition of ABL2 using allosteric inhibitors impairs expression of HSF1 protein and HSF1-E2F transcriptional gene targets. Collectively, these findings reveal a targetable ABL2-HSF1-E2F signaling pathway required for survival by brain-metastatic tumor cells.
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