Axl receptor tyrosine kinase expression in breast cancer

D’Alfonso, Timothy M.; Hannah, Jeffrey; Chen, Zhengming; Liu, Yifang; Zhou, Pengbo; Shin, Sandra J.

doi:10.1136/jclinpath-2013-202161

Cited by 53 publications

(58 citation statements)

References 33 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…S1) in 10 TNBC cell lines and found that AXL was significantly expressed in 7. These results are consistent with previous studies reporting that AXL is often upregulated in basal B and occasionally in basal A TNBC (20,21). Moreover, the cell lines in which AXL was most overexpressed (MDA-MB-231, BT549, HBL-100, BT20, and HS578T) are considered as highly invasive (22).…”

Section: Resultssupporting

confidence: 82%

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Leconet

Chentouf

Manoir

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation.

show abstract

Section: Resultssupporting

confidence: 82%

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Leconet

Chentouf

Manoir

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…S2). The observed percentage of AXL-positive TNBCs is consistent with recent previous reports (23,24).…”

Section: Axl Expression Correlates With a Mesenchymal Phenotypesupporting

confidence: 82%

AXL Inhibition Sensitizes Mesenchymal Cancer Cells to Antimitotic Drugs

Wilson¹,

Ye²,

Pham³

et al. 2014

Cancer Research

131

129

View full text Add to dashboard Cite

Molecularly targeted drug therapies have revolutionized cancer treatment; however, resistance remains a major limitation to their overall efficacy. Epithelial-to-mesenchymal transition (EMT) has been linked to acquired resistance to tyrosine kinase inhibitors (TKI), independent of mutational resistance mechanisms. AXL is a receptor tyrosine kinase associated with EMT that has been implicated in drug resistance and has emerged as a candidate therapeutic target. Across 643 human cancer cell lines that were analyzed, elevated AXL was strongly associated with a mesenchymal phenotype, particularly in triple-negative breast cancer and non-small cell lung cancer. In an unbiased screen of small-molecule inhibitors of cancer-relevant processes, we discovered that AXL inhibition was specifically synergistic with antimitotic agents in killing cancer cells that had undergone EMT and demonstrated associated TKI resistance. However, we did not find that AXL inhibition alone could overcome acquired resistance to EGFR TKIs in the EMT setting, as previously reported. These findings reveal a novel cotreatment strategy for tumors displaying mesenchymal features that otherwise render them treatment refractory. Cancer Res; 74(20); 5878-90. Ó2014 AACR.

show abstract

“…3, 5a and 5b). Although vimentin expression has been found to consistently be associated with TNBC [14,13,12,11], one study found that Axl expression, while associated with aggressive disease, did not segregate with TNBC but was found across ER negative and ER positive subtypes [15]. Thus, vimentin may be a more selective marker for the basal B TNBC.…”

Section: Discussionmentioning

confidence: 99%

“…While the basal A subtype retains a more epithelial phenotype, the basal B subtype possesses stem cell-like characteristics and also preferentially expresses specific markers, including the intermediate filament protein vimentin and receptor tyrosine kinase Axl [9]. Subsequent studies have explored using vimentin [11-14] or Axl [15] as TNBC/basal-like biomarkers in human breast tumors. Vimentin has been a particularly robust biomarker for TNBC, and vimentin and Axl have been associated with poor prognosis [11-15].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl

Dine

O’Sullivan

Voeller

et al. 2016

Breast Cancer Res Treat

View full text Add to dashboard Cite

Purpose Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand (TRAIL) preferentially killed triple negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5 specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. Methods We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African American women with TNBC. Results and Conclusions Drozitumab induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15% of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist.

show abstract

Axl receptor tyrosine kinase expression in breast cancer

Cited by 53 publications

References 33 publications

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis

AXL Inhibition Sensitizes Mesenchymal Cancer Cells to Antimitotic Drugs

The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl

Contact Info

Product

Resources

About