Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

AXL as a Target in Breast Cancer Therapy.

ABSTRACT: AXL is a receptor tyrosine kinase (RTK) that has been implicated in diverse tumor-promoting processes such as proliferation, migration, invasion, survival, and apoptosis. AXL therefore plays a role in cancer progression, and AXL has been implicated in a wide variety of malignancies from solid tumors to hematopoietic cancers where it is often associated with poor prognosis. In cancer, AXL has been shown to promote epithelial to mesenchymal transition (EMT), metastasis formation, drug resistance, and a role for AXL in modulation of the tumor microenvironment and immune response has been identified. In light of these activities multiple AXL inhibitors have been developed, and several of these have entered clinical trials in the U.S. In breast cancer, high levels of AXL expression have been observed. The role of AXL in cancer with a focus on therapeutic implications for breast cancer is discussed.

SUBMITTER: Colavito SA

PROVIDER: S-EPMC7042526 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

AXL as a Target in Breast Cancer Therapy.

Colavito Sierra A SA

Journal of oncology 20200214

AXL is a receptor tyrosine kinase (RTK) that has been implicated in diverse tumor-promoting processes such as proliferation, migration, invasion, survival, and apoptosis. AXL therefore plays a role in cancer progression, and AXL has been implicated in a wide variety of malignancies from solid tumors to hematopoietic cancers where it is often associated with poor prognosis. In cancer, AXL has been shown to promote epithelial to mesenchymal transition (EMT), metastasis formation, drug resistance, ...[more]

PMID: 32148495

Similar Datasets

AXL kinase as a novel target for cancer therapy.

Project description:The AXL receptor tyrosine kinase and its major ligand, GAS6 have been demonstrated to be overexpressed and activated in many human cancers (such as lung, breast, and pancreatic cancer) and have been correlated with poor prognosis, promotion of increased invasiveness/metastasis, the EMT phenotype and drug resistance. Targeting AXL in different model systems with specific small molecule kinase inhibitors or antibodies alone or in combination with other drugs can lead to inactivation of AXL-mediated signaling pathways and can lead to regained drug sensitivity and improved therapeutic efficacy, defining AXL as a promising novel target for cancer therapeutics. This review highlights the data supporting AXL as a novel treatment candidate in a variety of cancers as well as the current status of drug development targeting the AXL/GAS6 axis and future perspectives in this emerging field.

| S-EPMC4259419 | biostudies-literature

Axl receptor tyrosine kinase expression in breast cancer.

Project description:AimsTriple-negative breast cancer comprises a clinically aggressive group of invasive carcinomas. We examined a published gene expression screen of a panel of breast cancer cell lines to identify a potential triple-negative breast cancer-specific gene signature, and attempted to verify our findings by performing immunohistochemical analysis on tissue microarrays containing a large cohort of invasive breast carcinomas.MethodsThe microarray dataset for a panel of human breast cancer cell lines was interrogated for triple-negative breast cancer-specific genes. Membranous immunohistochemical expression of the protein product of the AXL gene was assessed semiquantitatively in 569 invasive breast carcinomas grouped according to molecular subgroup by immunohistochemistry.ResultsAXL was significantly upregulated in triple-negative/basal B cell lines compared with luminal or basal A cell lines. No significant difference was observed in the level of immunohistochemical expression of Axl protein between triple-negative breast cancers and other molecular subgroups (p=0.257). Axl expression was significantly associated with lymphovascular invasion (LVI) in all subgroups combined (p=0.033), and within the luminal A (p=0.002) and triple-negative breast cancer subgroups (p=0.026).ConclusionsDespite preferential upregulation of AXL in triple-negative/basal B cell lines, analysis of Axl protein expression in a large series of patients' breast tumours revealed no association between Axl expression and triple-negative breast cancer or other subtype. The association of Axl expression with LVI supports previous work that implicates Axl as a promoter of invasiveness in breast cancer cell lines. Further studies are necessary to explore whether Axl expression of individual breast cancer tumours can be clinically useful.

| S-EPMC4549806 | biostudies-literature

Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA.

Project description:The identification of molecular features that contribute to the progression of breast cancer can provide valuable insight into the pathogenesis of this disease. Deregulated microRNA expression represents one type of molecular event that has been associated with many different human cancers. In order to identify a miRNA/mRNA regulatory interaction that is biologically relevant to the triple-negative breast cancer genotype/phenotype, we initially conducted a miRNA profiling experiment to detect differentially expressed miRNAs in cell line models representing triple-negative (MDA-MB-231), ER(+) (MCF7), and HER-2 overexpressed (SK-BR-3) histotypes. We identified human miR-34a expression as being >3-fold down (from its median expression value across all cell lines) in MDA-MB-231 cells, and identified AXL as a putative mRNA target using multiple miRNA/target prediction algorithms. The miR-34a/AXL interaction was functionally characterized through ectopic overexpression experiments with a miR-34a mimic in two independent triple-negative breast cancer cell lines. In reporter assays, miR-34a binds to its putative target site within the AXL 3'UTR to inhibit luciferase expression. We also observed degradation of AXL mRNA and decreased AXL protein levels, as well as cell signaling effects on AKT phosphorylation and phenotypic effects on cell migration. Finally, we present an inverse correlative trend in miR-34a and AXL expression for both cell line and patient tumor samples.

| S-EPMC3381742 | biostudies-literature

AXL in cancer: a modulator of drug resistance and therapeutic target.

Project description:AXL is a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases family (RTKs), and its abnormal expression has been linked to clinicopathological features and poor prognosis of cancer patients. There is mounting evidence supporting AXL's role in the occurrence and progression of cancer, as well as drug resistance and treatment tolerance. Recent studies revealed that reducing AXL expression can weaken cancer cells' drug resistance, indicating that AXL may be a promising target for anti-cancer drug treatment. This review aims to summarize the AXL's structure, the mechanisms regulating and activating it, and its expression pattern, especially in drug-resistant cancers. Additionally, we will discuss the diverse functions of AXL in mediating cancer drug resistance and the potential of AXL inhibitors in cancer treatment.

| S-EPMC10273696 | biostudies-literature

Does Axl have potential as a therapeutic target in pancreatic cancer?

Project description:IntroductionPancreatic cancer is a leading cause of cancer-related death. Metastasis, therapy resistance, and immunosuppression are dominant characteristics of pancreatic tumors. Strategies that enhance the efficacy of standard of care and/or immune therapy are likely the most efficient route to improve overall survival in this disease. Areas covered: Axl, a member of the TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases, is involved in cell plasticity, chemoresistance, immune suppression, and metastasis in various cancers, including pancreatic cancer. This review provides an overview of Axl and its function in normal conditions, summarizes the regulation and function of Axl in cancer, and highlights the contribution of Axl to pancreatic cancer as well as its potential as a therapeutic target. Expert opinion: Axl is an attractive therapeutic target in pancreatic cancer because it contributes to many of the roadblocks that hamper therapeutic efficacy. Clinical evidence supporting Axl inhibition in pancreatic cancer is currently limited; however, multiple clinical trials have been initiated or are in the planning phase to test the effect of inhibiting Axl in conjunction with standard therapy in pancreatic cancer patients. We anticipate that these studies will provide robust validation of Axl as a therapeutic target in pancreatic cancer.

| S-EPMC6292430 | biostudies-literature

AXL Receptor in Breast Cancer: Molecular Involvement and Therapeutic Limitations.

Project description:Breast cancer was one of the first malignancies to benefit from targeted therapy, i.e., treatments directed against specific markers. Inhibitors against HER2 are a significant example and they improved the life expectancy of a large cohort of patients. Research on new biomarkers, therefore, is always current and important. AXL, a member of the TYRO-3, AXL and MER (TAM) subfamily, is, today, considered a predictive and prognostic biomarker in many tumor contexts, primarily breast cancer. Its oncogenic implications make it an ideal target for the development of new pharmacological agents; moreover, its recent role as immune-modulator makes AXL particularly attractive to researchers involved in the study of interactions between cancer and the tumor microenvironment (TME). All these peculiarities characterize AXL as compared to other members of the TAM family. In this review, we will illustrate the biological role played by AXL in breast tumor cells, highlighting its molecular and biological features, its involvement in tumor progression and its implication as a target in ongoing clinical trials.

| S-EPMC7696061 | biostudies-literature

Axl-148b chimeric aptamers inhibit breast cancer and melanoma progression.

Project description:microRNAs (miRNAs) are small non-coding RNAs acting as negative regulators of gene expression and involved in tumor progression. We recently showed that inhibition of the pro-metastatic miR-214 and simultaneous overexpression of its downstream player, the anti-metastatic miR-148b, strongly reduced metastasis formation. To explore the therapeutic potential of miR-148b, we generated a conjugated molecule aimed to target miR-148b expression selectively to tumor cells. Precisely, we linked miR-148b to GL21.T, an aptamer able to specifically bind to AXL, an oncogenic tyrosine kinase receptor highly expressed on cancer cells. Axl-148b conjugate was able to inhibit migration and invasion of AXL-positive, but not AXL-negative, cancer cells, demonstrating high efficacy and selectivity in vitro. In parallel, expression of ALCAM and ITGA5, two miR-148b direct targets, was reduced. More importantly, axl-148b chimeric aptamers were able to inhibit formation and growth of 3D-mammospheres, to induce necrosis and apoptosis of treated xenotransplants, as well as to block breast cancer and melanoma dissemination and metastatization in mice. Relevantly, axl aptamer acted as specific delivery tool for miR-148b, but it also actively contributed to inhibit metastasis formation, together with miR-148b. In conclusion, our data show that axl-148b conjugate is able to inhibit tumor progression in an axl- and miR-148b-dependent manner, suggesting its potential development as therapeutic molecule.

| S-EPMC7053324 | biostudies-literature

Engineering Axl specific CAR and SynNotch receptor for cancer therapy.

Project description:Axl is a tyrosine kinase receptor that is commonly overexpressed in many cancers. As such, Axl represents an attractive therapeutic target. The transfer of engineered T cell expressing chimeric antigen receptor (CAR) is an exciting cancer therapeutic approach that shows high efficacy against cancers in clinical trials, especially for B cell malignancies. Furthermore, recently developed synthetic Notch (synNotch) receptor has demonstrated potential in enhancing the specificity of CAR T cell therapy and delivering therapeutic payloads to tumors in an antigen-dependent manner. Therefore, a CAR or synNotch against Axl could be a valuable therapeutic reagent against many cancers. Here, we develop a single-chain variable fragment from a humanized monoclonal antibody against Axl. The scFv is attached to CD3ζ, CD28, and 4-1BB signaling domains to generate an anti-Axl CAR. When introduced into human primary T cells, the anti-Axl CAR can lead to cytokine production and cell killing in response to tumor cells expressing Axl. Moreover, an anti-Axl synNotch generated using the same scFv can be activated with Axl expressing tumor cells. Given the fact that Axl is an important cancer therapeutic target, these receptors could be valuable reagents for developing anti-Axl therapies.

| S-EPMC5832765 | biostudies-literature

AXL is an essential factor and therapeutic target for metastatic ovarian cancer.

Project description: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.

| S-EPMC3408227 | biostudies-literature

AXL Controls Directed Migration of Mesenchymal Triple-Negative Breast Cancer Cells.

Project description:Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with high risk of relapse and metastasis. TNBC is a heterogeneous disease comprising different molecular subtypes including those with mesenchymal features. The tyrosine kinase AXL is expressed in mesenchymal cells and plays a role in drug resistance, migration and metastasis. We confirm that AXL is more expressed in mesenchymal TNBC cells compared to luminal breast cancer cells, and that its invalidation impairs cell migration while having no or little effect on cell viability. Here, we found that AXL controls directed migration. We observed that AXL displays a polarized localization at the Golgi apparatus and the leading edge of migratory mesenchymal TNBC cells. AXL co-localizes with F-actin at the front of the cells. In migratory polarized cells, the specific AXL inhibitor R428 displaces AXL and F-actin from the leading edge to a lateral area localized between the front and the rear of the cells where both are enriched in protrusions. In addition, R428 treatment disrupts the polarized localization of the Golgi apparatus towards the leading edge in migratory cells. Immunohistochemical analysis of aggressive chemo-resistant TNBC samples obtained before treatment reveals inter- and intra-tumor heterogeneity of the percentage of AXL expressing tumor cells, and a preference of these cells to be in contact with the stroma. Taken together, our study demonstrates that AXL controls directed cell migration most likely by regulating cell polarity.

| S-EPMC7016818 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data