Research ArticleCancer

The GAS6-AXL signaling network is a mesenchymal (Mes) molecular subtype–specific therapeutic target for ovarian cancer

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Science Signaling  04 Oct 2016:
Vol. 9, Issue 448, pp. ra97
DOI: 10.1126/scisignal.aaf8175

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Personalizing treatment for ovarian cancer

Most patients with ovarian cancer have advanced-stage disease at diagnosis, and treatment options are mainly palliative. Among the various subtypes of ovarian cancer, the mesenchymal (“Mes”) subtype is particularly aggressive. Antony et al. searched for therapeutic options specific for patients with Mes-type tumors by comparing kinase activity profiles in Mes-type and epithelial (“Epi”)–type tumor cells. Relative to Epi-type cells, an increased abundance and distinct localization and activity signature of the receptor tyrosine kinase AXL were associated with metastatic phenotypes in Mes-type cells. AXL inhibition with the small-molecule drug R428 made the Mes-type tumor cells more “Epi-type” and increased survival in tumor-bearing mice. Thus, AXL inhibitors may halt tumor progression and prolong survival in patients with advanced ovarian cancer.


Ovarian cancer is a complex disease with heterogeneity among the gene expression molecular subtypes (GEMS) between patients. Patients with tumors of a mesenchymal (“Mes”) subtype have a poorer prognosis than patients with tumors of an epithelial (“Epi”) subtype. We evaluated GEMS of ovarian cancer patients for molecular signaling profiles and assessed how the differences in these profiles could be leveraged to improve patient clinical outcome. Kinome enrichment analysis identified AXL as a particularly abundant kinase in Mes-subtype tumor tissue and cell lines. In Mes cells, upon activation by its ligand GAS6, AXL coclustered with and transactivated the receptor tyrosine kinases (RTKs) cMET, EGFR, and HER2, producing sustained extracellular signal–regulated kinase (ERK) activation. In Epi-A cells, AXL was less abundant and induced a transient activation of ERK without evidence of RTK transactivation. AXL-RTK crosstalk also stimulated sustained activation of the transcription factor FRA1, which correlated with the induction of the epithelial-mesenchymal transition (EMT)–associated transcription factor SLUG and stimulation of motility exclusively in Mes-subtype cells. The AXL inhibitor R428 attenuated RTK and ERK activation and reduced cell motility in Mes cells in culture and reduced tumor growth in a chick chorioallantoic membrane model. A higher concentration of R428 was needed to inhibit ERK activation and cell motility in Epi-A cells. Silencing AXL in Mes-subtype cells reversed the mesenchymal phenotype in culture and abolished tumor formation in an orthotopic xenograft mouse model. Thus, AXL-targeted therapy may improve clinical outcome for patients with Mes-subtype ovarian cancer.

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