A TAZ-AXL-ABL2 Feed-Forward Signaling Axis Promotes Lung Adenocarcinoma Brain Metastasis

Highlights

• TAZ drives lung cancer brain metastases via transcription of ABL2, AXL, and L1CAM

• AXL, ABL2, and TAZ engage in an autocrine feed-forward loop during brain metastasis

• Knockdown of AXL or ABL2 kinases decreases lung adenocarcinoma brain metastases

• Allosteric ABL kinase inhibitor ABL001 crosses the BBB and impairs brain metastases

Summary

Brain metastases are a common consequence of advanced lung cancer, resulting in cranial neuropathies and increased mortality. Currently, there are no effective therapies to treat brain metastases due to a lack of actionable targets and a failure of systemic therapies to penetrate the blood-brain barrier (BBB). Here we identify an autocrine signaling axis required for lung adenocarcinoma brain metastasis, whereby nuclear accumulation of the TAZ transcriptional co-activator drives expression of a panel of transcripts enriched in brain metastases, including ABL2 and AXL, encoding for protein tyrosine kinases that engage in bidirectional signaling. Activation of ABL2 in turn promotes TAZ tyrosine phosphorylation and nuclear localization, establishing an autocrine AXL-ABL2-TAZ feed-forward signaling loop required for brain metastasis colonization. Notably, treatment with a BBB-penetrant ABL allosteric inhibitor or knockdown of ABL2, AXL, or TAZ markedly decreases brain metastases. These findings suggest that ABL and AXL inhibitors might be effective against brain metastases.