Targeting AXL can effectively inhibit c-Met-induced therapeutic resistance in renal cancer
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PROVIDER: PRJNA1257779 | ENA |
REPOSITORIES: ENA
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Project description:The mechanism(s) for therapeutic resistance against c-Met/receptor tyrosine kinase (RTK) inhibitor(s) in renal cancer is totally unexplored. In renal cell carcinoma (RCC) cells, both AXL and c-Met are highly overexpressed and they form a complex. Interestingly, the prolonged treatment with c-Met/RTK inhibitor, Cabozantinib (Cabo), which is being used for the treatment of RCC patients, markedly increased the level of total c-Met and promoted renal cancer cell proliferation. This effect was confirmed not only in vitro but also in murine models and renal tumor tissues from Cabo-treated patients. Also, the lower concentrations of Cabo treatment could not inhibit HGF (c-Met ligand)-induced c-Met phosphorylation; rather they further increased the phosphorylation of the receptor and promoted downstream signaling events for tumor growth. In addition, our findings indicate that Cabo treatment induces AXL-c-Met association, and it interferes with the physiological degradation processes of c-Met within renal cancer cells. However, either the inhibition or the knockout of AXL could significantly overcome the therapeutic resistance against c-Met inhibitor(s); and it markedly induced apoptotic cell death through increased oxidative stress and inhibition of the transcription factor, Nrf2. We generated Cabo-resistant RCC cells, and we observed that the expression of both c-Met and AXL are markedly overexpressed in these cells; and the inhibition of AXL (through TP-0903) can resensitize the cancer cells to Cabo-mediated cell death. Moreover, we found significant differences in the epigenomic profile of the Cabo-resistant RCC cells compared with Cabo-sensitive cancer cells. Our in-depth studies suggest that AXL plays a major role in mediating therapeutic resistance against c-Met inhibitor(s). A combination therapy using c-Met inhibitor(s) in the presence of an AXL inhibitor can play a pivotal role to overcome acquired resistance against RTK inhibitors in renal cancer.
2025-09-10 | GSE296078 | GEO
Project description:Nephron epithelial cells arise through a mesenchymal-to-epithelial transition (MET) during kidney development. We used scRNA-seq and multi-ome profiling to investigate transcriptional mechanisms driving MET in human renal organoids.
2024-02-01 | GSE232787 | GEO
Project description:Aortic remodeling is a cause and consequence of hypertension. It increases workload on the heart and enhances arterial pulsatility in the microcirculation. We have shown that excessive endothelial stretch leads to release of Growth Arrest Specific 6 (GAS6), which in turn activates the tyrosine kinase receptor Axl on monocytes, and causes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model aortic remodeling in mice following a 2-week infusion of angiotensin II (ang II). Aortas demonstrated increased mural collagen and mechanical testing revealed a marked loss of Windkessel function or energy storage that persisted for 6 months following ang II. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria and tubular damage as estimated by Periodic Acid Schiff (PAS) staining. Treatment with the Axl inhibitor R428 beginning 2 months after ang II infusion had minimal effect on aortic remodeling 2 months later, but reduced the infiltration of T cells, g/d T cells and macrophages into the aorta and kidney, and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. We conclude that brief episodes of hypertension can induce chronic aortic remodeling which in turn associates with a low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.
2022-12-31 | GSE205267 | GEO
Project description:We report the comparative investigation of gene expression profiles between genetic inactivation AXL cell and AXL wild type cells in two independent We found a list of AXL signaling target genes that are important for tumor invasion and angiogenesis.
2020-04-03 | GSE125994 | GEO
Project description:We evaluated soluble AXL (sAXL or batiraxcept), a decoy receptor that can potently inhibit AXL signaling, as a single agent or in combination with docetaxel or carboplatin to treat prostate cancer (PCa) bone metastases. We used intratibial injection of multiple patient-derived xenografts with different characteristics, reflecting a traditional phase II clinical trial without pre-selection for a particular tumor characteristic. Inhibition of tyrosine kinase receptor AXL was highly effective as a single agent and showed additive effects when combined with docetaxel or carboplatin in suppressing PCa tumor growth in the bone and in suppressing metastasis to the lung. AXL inhibition suppressed critical cancer stem cell gene expression and significantly decreased proliferation and metastasis through suppression of E2F1 and NuSAP1. Our findings provide compelling preclinical data for testing batiraxcept in patients with prostate cancer with bone metastases.
2025-01-23 | GSE281461 | GEO
Project description:Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas as well as in other cancers. These mutations have been examined in several in vitro systems, where they cause constitutive Met activation, focus formation, and cell motility, and are tumorigenic in xenografts. To determine the influence of these mutations on tumorigenesis in vivo, we generated mice with targeted mutations in the murine met locus. Five mouse lines with mutant Met were created: wt, D1226N, Y1228C, M1248T, and M1248T/L1193V. These mouse lines develop a wide range of sarcomas, lymphomas, and carcinomas. To determine if mutationally activated forms of Met have altered signaling specificity we utilized gene expression analysis. Mouse embryonic fibroblasts (MEFs) were isolated from the mutant Met lines and here we present data for wild type and M1248T (M833). Our results indicate that Met activating mutations have unique gene expression signatures. Keywords: mutant analysis Color swapped replicates with common reference
2011-11-20 | E-GEOD-11319 | biostudies-arrayexpress
Project description:Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas as well as in other cancers. These mutations have been examined in several in vitro systems, where they cause constitutive Met activation, focus formation, and cell motility, and are tumorigenic in xenografts. To determine the influence of these mutations on tumorigenesis in vivo, we generated mice with targeted mutations in the murine met locus. Five mouse lines with mutant Met were created: wt, D1226N, Y1228C, M1248T, and M1248T/L1193V. These mouse lines develop a wide range of sarcomas, lymphomas, and carcinomas. To determine if mutationally activated forms of Met have altered signaling specificity we utilized gene expression analysis. Mouse embryonic fibroblasts (MEFs) were isolated from the mutant Met lines and here we present data for wild type and M1248T (M833). Our results indicate that Met activating mutations have unique gene expression signatures. Keywords: mutant analysis
2011-11-20 | GSE11319 | GEO
Project description:AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. We report that AXL is also detected in HER2+ breast cancer specimens where its expression correlates with poor patients’ survival. Using murine models of HER2+ breast cancer, AXL, but not Gas6, was found essential for metastasis. We determined that AXL is required for intravasation, extravasation and growth at the metastatic site. AXL is expressed in HER2+ cancers displaying EMT signatures and contributes to sustain EMT in murine tumors. Interfering with AXL in patient-derived xenograft impaired TGF-β-induced cell invasion. Lastly, pharmacological inhibition of AXL decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential co-therapeutic target during the treatment of HER2+ breast cancers to limit metastasis.
2018-05-01 | GSE102368 | GEO
Project description:The activation of bypass signals, such as MET and AXL, has been identified as a possible mechanism of EGFR-TKI resistance. Because various oncoproteins depend on HSP90 for maturation and stability, we investigated the effects of AUY922, a newly developed non-geldanamycin class HSP90 inhibitor, in lung cancer cells with MET- and AXL-mediated resistance. We established resistant cell lines with HCC827 cells harboring an exon 19-deletion mutation in of the EGFR gene via long-term exposure to increasing concentrations of gefitinib and erlotinib (HCC827/GR and HCC827/ER, respectively). HCC827/GR resistance was mediated by MET activation, whereas AXL activation caused resistance in HCC827/ER cells. AUY922 treatment effectively suppressed proliferation and induced cell death in both resistant cell lines. Accordingly, the downregulation of EGFR, MET, and AXL led to decreased Akt activation. The inhibitory effects of AUY922 on each receptor were confirmed in gene-transfected LK2 cells. AUY922 also effectively controlled tumor growth in xenograft mouse models containing HCC827/GR and HCC827/ER cells. In addition, AUY922 reduced invasion and migration by both types of resistant cells. Our study findings thus show that AUY922 is a promising therapeutic option for MET- and AXL-mediated resistance to EGFR-TKI in lung cancer.
| S-EPMC4363657 | biostudies-literature
Project description:KSHV is a principal causative agent of primary effusion lymphoma (PEL). Despite this knowledge about the close relationship between HGF/c-MET network and solid tumors development, the role of HGF/c-MET in KSHV-related malignancies remains mostly unclear. We report that HGF/c-MET pathway is highly active within KSHV+ PEL cells and plays important role in tumor cell survival/growth. Targeting HGF/c-MET by a selective inhibitor, PF-2341066, significantly induces PEL apoptosis through a complex of underlying mechanisms, including cell-cycle arrest and DNA damage. By using microarray analysis, we have identified the global gene profile controlled by HGF/c-MET pathway within KSHV+ PEL cell-lines and several novel âdruggableâ candidates closely related to cancer cell survival/growth. Finally, we found that targeting HGF/c-MET pathway by PF-2341066 effectively prevents PEL tumor expansion and/or reduce established lymphoma progression in vivo. PEL cells were treated with vehicle control or c-MET inhibitor PF-2341066 (0.8 µM) for 24 h, and the gene expression signature was compared to respective vehicle controls
2016-01-05 | E-GEOD-70594 | biostudies-arrayexpress