An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies

Ye, X; Li, Y; Stawicki, Scott; Couto, Suzana; Eastham-Anderson, Jeffrey; Kallop, Dara; Weimer, Robby M.; Wu, Yan; Pei, Lirong

doi:10.1038/onc.2010.268

Cited by 200 publications

(180 citation statements)

References 41 publications

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“…Small molecule inhibitors of the TAM receptors may be reasonable candidates for potential therapies in acute sepsis and for new generation of vaccine adjuvants for immunization (71). Also, it has to be mentioned that other ways to regulate the activation of Axl are being developed, such as monoclonal antibodies targeting the kinase or its ligand Gas6, as well as aptamers to downregulate its expression (72,73).…”

Section: Discussionmentioning

confidence: 99%

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Feneyrolles¹,

Spenlinhauer²,

Guiet³

et al. 2014

Molecular Cancer Therapeutics

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Receptor tyrosine kinases (RTK) are transmembrane receptors that regulate signal transduction in cells. As a member of the TAM (Tyro-3, Axl, Mer) RTK subfamily, Axl regulates key processes such as cell growth, migration, aggregation, and apoptosis through several pathways. Its overexpression/overactivation has been underlined in several conditions, especially cancers, and in both chemotherapy and targeted therapy sensitivity loss. In this review, we propose to highlight the therapeutic implication of Axl, starting with the pathways it regulates, validating its interest as a therapeutic target, and defining the tools available to develop strategies for its inhibition. We especially focus on small molecule inhibitors, their structure, inhibition profile, and development stages. Mol Cancer Ther; 13(9); 2141-8. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Feneyrolles¹,

Spenlinhauer²,

Guiet³

et al. 2014

Molecular Cancer Therapeutics

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“…Overexpression of AXL has been reported as a mechanism of acquired lapatinib resistance in breast cancer cells (49), acquired imatinib resistance in gastrointestinal stromal tumors (50), and most recently erlotinib resistance in NSCLC cells and patient specimens (15). In addition, an anti-AXL monoclonal antibody YW327.6S2 has been reported to enhance the effect of erlotinib in NSCLC models (51). PI3K is a potential downstream mediator of AXL signaling (52), suggesting that AXL overexpression might be responsible for the observed activation of the PI3K pathway in our HCC827 erlotinib-TR clones.…”

Section: Discussionmentioning

confidence: 99%

Potential Advantages of CUDC-101, a Multitargeted HDAC, EGFR, and HER2 Inhibitor, in Treating Drug Resistance and Preventing Cancer Cell Migration and Invasion

Wang

Pursell

Samson

et al. 2013

Molecular Cancer Therapeutics

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CUDC-101 is a novel, small-molecule, anticancer agent targeting histone deacetylase (HDAC), EGF receptor (EGFR), and HER2. It is currently in phase I clinical development in patients with solid tumors. Previously, we reported that CUDC-101 has potent antiproliferative and proapoptotic activity in cultured tumor cells and in vivo xenograft models. We now show that cancer cells that have acquired resistance to single-target EGFR inhibitors through upregulation of AXL or loss of E-cadherin remain sensitive to CUDC-101, which inhibits MET-and AXL-mediated signaling, restores E-cadherin expression, and reduces cell migration. CUDC-101 also efficiently inhibited the proliferation of MET-overexpressing non-small cell lung cancer and gastric cancer cell lines and inhibited the migration and invasion of invasive tumor cells. Taken together, these results suggest that coupling HDAC and HER2 inhibitory activities to an EGFR inhibitor may potentially be effective in overcoming drug resistance and preventing cancer cell migration. Mol Cancer Ther; 12(6); 925-36. Ó2013 AACR.

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“…This context might have an effect on AXL expression and role that only clinical trial, targeting the receptor with an antibody or a TKI, would be able to answer. Today, various AXL-specific TKIs (5,29,30) and mAbs (14,31,32) have been tested in preclinical models and only one AXL inhibitor, BGB324 (R428), is evaluated in clinical trials for acute myeloid leukemia (33). Phase I studies demonstrated that BGB324 could be safely administered for prolonged periods at doses that inhibit AXL activation and exhibit antileukemic activity.…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies

Cited by 200 publications

References 41 publications

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

Potential Advantages of CUDC-101, a Multitargeted HDAC, EGFR, and HER2 Inhibitor, in Treating Drug Resistance and Preventing Cancer Cell Migration and Invasion

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

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