Article

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: 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.
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