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.
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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.
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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.
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Project description:Cancer often involves aberrant epigenetic activation. In CML-BP, super - enhancer - driven SOX4 and SMAD3 form an auto - regulatory axis. They co - regulate epigenome, activate AXL - related pathways, and mediate membrane phospholipid remodeling. Bemcentinib, an AXL inhibitor, can inhibit CML - BP progression. SOX4/SMAD3 are key factors and Bemcentinib a potential therapy.
2026-05-15 | GSE292718 | GEO
Project description:Cancer often involves aberrant epigenetic activation. In CML-BP, super - enhancer - driven SOX4 and SMAD3 form an auto - regulatory axis. They co - regulate epigenome, activate AXL - related pathways, and mediate membrane phospholipid remodeling. Bemcentinib, an AXL inhibitor, can inhibit CML - BP progression. SOX4/SMAD3 are key factors and Bemcentinib a potential therapy.
2026-05-15 | GSE292717 | GEO
Project description:Cancer often involves aberrant epigenetic activation. In CML-BP, super - enhancer - driven SOX4 and SMAD3 form an auto - regulatory axis. They co - regulate epigenome, activate AXL - related pathways, and mediate membrane phospholipid remodeling. Bemcentinib, an AXL inhibitor, can inhibit CML - BP progression. SOX4/SMAD3 are key factors and Bemcentinib a potential therapy.
2026-05-15 | GSE292716 | 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