AXL Is an Essential Factor and Therapeutic Target for Metastatic Ovarian Cancer

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University, Stanford, California 94305-5152, USA.
Cancer Research (Impact Factor: 9.28). 10/2010; 70(19):7570-9. DOI: 10.1158/0008-5472.CAN-10-1267
Source: PubMed

ABSTRACT The receptor tyrosine kinase AXL is thought to play a role in metastasis; however, the therapeutic efficacy of an AXL-targeting agent remains largely untested in metastatic disease. In this study, we defined AXL as a therapeutic target for metastatic ovarian cancer. AXL is primarily expressed in metastases and advanced-stage human ovarian tumors but not in normal ovarian epithelium. Genetic inhibition of AXL in human metastatic ovarian tumor cells is sufficient to prevent the initiation of metastatic disease in vivo. Mechanistically, inhibition of AXL signaling in animals with metastatic disease results in decreased invasion and matrix metalloproteinase activity. Most importantly, soluble human AXL receptors that imposed a specific blockade of the GAS6/AXL pathway had a profound inhibitory effect on progression of established metastatic ovarian cancer without normal tissue toxicity. These results offer the first genetic validation of GAS6/AXL targeting as an effective strategy for inhibition of metastatic tumor progression in vivo. Furthermore, this study defines the soluble AXL receptor as a therapeutic candidate agent for treatment of metastatic ovarian cancer, for which current therapies are ineffective.

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    • "The PI3K signaling pathway has been shown to be a downstream effector of Axl in cancer cells, and its activation was described as correlating with higher levels of Axl expression (Lee et al., 2002; Ruan and Kazlauskas, 2012; Paccez et al., 2013). Activation of Akt by Axl leads to phosphorylation of IKKα and consequent phosphorylation, ubiquitination, and degradation of IκBα, triggering the activation of NF-κB (Gjerdrum et al., 2010; Rankin et al., 2010; Paccez et al., 2013). "
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    ABSTRACT: The receptor tyrosine kinase Axl has been described as an oncogene and its deregulation has been implicated in the progression of several human cancers. While the role of Axl in oesophageal adenocarcinoma has been addressed, there is no information about its role in oesophageal squamous cell carcinoma. In the current report, we identified, for the first time, deregulation of Axl expression in oesophageal squamous cell carcinoma (OSCC). Axl is consistently overexpressed in OSCC cell lines and human tumor samples, mainly in advanced stages of the disease. Blockage of Axl gene expression by small interfering RNA inhibits cell survival, proliferation, migration, and invasion in vitro and oesophageal tumor growth in vivo. Additionally, repression of Axl expression results in Akt-dependent inhibition of pivotal genes involved in the NF-κB pathway and in the induction of GSK3β activity, resulting in loss of mesenchymal and induction of epithelial markers. Furthermore, treatment of oesophageal cancer cells with the Akt inhibitor wortmannin inhibits NF-κB signaling, induces GSK3β activity and blocks OSCC cell proliferation in an Axl-dependent manner. Taken together, our results establish a clear role for Axl in OSCC tumorigenesis with potential therapeutic implications. © 2015 by The American Society for Cell Biology.
    Molecular Biology of the Cell 01/2015; DOI:10.1091/mbc.E14-04-0868
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    ABSTRACT: Thyroid cancer is the most common endocrine cancer, but its key oncogenic drivers remain undefined. In this study we identified the TYRO3 and AXL receptor tyrosine kinases as transcriptional targets of the chemokine CXCL12/SDF-1 in CXCR4-expressing thyroid cancer cells. Both receptors were constitutively expressed in thyroid cancer cell lines but not normal thyroid cells. AXL displayed high levels of tyrosine phosphorylation in most cancer cell lines due to constitutive expression of its ligand GAS6. In human thyroid carcinoma specimens, but not in normal thyroid tissues, AXL and GAS6 were often coexpressed. In cell lines expressing both receptors and ligand, blocking each receptor or ligand dramatically affected cell viability and decreased resistance to apoptotic stimuli. Stimulation of GAS6-negative cancer cells with GAS6 increased their proliferation and survival. Similarly, siRNA-mediated silencing of AXL inhibited cancer cell viability, invasiveness, and growth of tumor xenografts in nude mice. Our findings suggest that a TYRO3/AXL-GAS6 autocrine circuit sustains the malignant features of thyroid cancer cells and that targeting the circuit could offer a novel therapeutic approach in this cancer.
    Cancer Research 02/2011; 71(5):1792-804. DOI:10.1158/0008-5472.CAN-10-2186
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    ABSTRACT: Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscle-invasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels.
    Oncogene 08/2011; 31(12):1493-503. DOI:10.1038/onc.2011.336
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