Lung cancer is the leading cause of cancer mortality in the U.S., with an overall five-year survival rate of ~16%. Notably, lung cancer patients exhibit the highest prevalence of brain metastasis (40-60 %) among all cancer types. Brain metastases often result in functional impairment, cranial neuropathies, and increased mortality. Currently, there are no effective therapies to treat brain metastases primarily due to a lack of actionable targets and the failure of systemic therapies to penetrate the blood-brain barrier (BBB). Unexpectedly, we found that expression of an active form of TAZ (TAZ-4SA) resistant to ubiquitin-dependent degradation, in lung adenocarcinoma cells promoted metastasis predominantly to the brain (Fig. 1 A-C), and that depletion of TAZ from brain metastatic lung cancer cells inhibited brain metastases and prolonged survival in mice following intra-cardiac injection (Fig. 1 D-F). Thus, TAZ is necessary and sufficient for lung adenocarcinoma metastasis.
Fig. 1. Active TAZ is necessary and sufficient to promote lung adenocarcinoma brain metastases. (A) Representative BLI of PC9 parental or active TAZ (TAZ4SA)-expressing PC9 lung cancer cells labeled with luciferase reporter and injected intracardially. (B) Survival curves depicting brain metastasis-free survival (BMFS). (C) Quantitative analysis of brain-metastatic burden in mice injected intracardially with parental or TAZ4SA cells. (D) Representative BLI and (E) BMFS survival curves of mice injected with PC9-BrM3 cells transduced with shRNAs against non-target control (shNTC) or TAZ knockdown (shTAZ). (F) Immunoblot analysis of PC9-BrM3 cells from D and E transduced with NTC and TAZ shRNAs. ** p-value < 0.01.
We identified 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 tyrosine phosphorylation of TAZ and drives TAZ nuclear localization. Establishment of this AXL-ABL2-TAZ autocrine feed-forward signaling loop promotes expression of a set of transcripts linked to development of brain metastasis (Fig. 2). Notably, treatment with a BBB-penetrant ABL allosteric inhibitor or knockdown of ABL2, AXL or TAZ in lung cancer cells markedly decreases disease burden and prolongs survival in mice. These findings suggest that ABL and AXL kinase inhibitors might be employed as therapies for the treatment of lung cancer brain metastases. These findings were published in Cell Reports 29: 3421-3434, December 10, 2019.
