title: The GAS6-AXL signaling network is a mesenchymal (Mes) molecular subtype-specific therapeutic target for ovarian cancer.
abstract: 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 117456, Singapore. Department of Surgery and Cancer, Imperial College London, London W120NN, U.K.
authors.forename: Jane
authors.initials: J
authors.lastname: Antony
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W120NN, U.K.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Kelly
authors.affiliation: Department of Obstetrics and Gynecology, National University Health System, Singapore 119228, Singapore.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Low
authors.affiliation: Department of Obstetrics and Gynecology, National University Health System, Singapore 119228, Singapore.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Choolani
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W120NN, U.K.
authors.forename: Chiara
authors.initials: C
authors.lastname: Recchi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W120NN, U.K.
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore. Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore. Department of Obstetrics and Gynecology, National University Health System, Singapore 119228, Singapore. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore. ruby_yj_huang@nuhs.edu.sg.
authors.forename: Ruby Yun-Ju
authors.initials: RY
authors.lastname: Huang
mesh_terms: D000818:Animals; D001567:Benzocycloheptenes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002642:Chick Embryo; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D001567:Benzocycloheptenes; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D014230:Triazoles; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C548378:bemcentinib