AXL Inhibitors: Status of Clinical Development

Bhalla, Sheena; Gerber, David E.

doi:10.1007/s11912-023-01392-7

Cited by 13 publications

(11 citation statements)

References 64 publications

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“…1 a), it is required for the maintenance of mesenchymal phenotype in vitro and in vivo 13 , 42 and several small molecule AXL inhibitors are currently being investigated in clinical settings. In particular, AXL inhibitor Dubermatinib (TP-0903) has shown promise in a clinical trial investigating AML patients’ response to combination treatment with decitabine 43 . Thus, we tested whether TP-0903 cooperated with ART in inducing cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate

Terragno,

Vetrova,

Semenov

et al. 2024

Sci Rep

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Triple-negative breast cancer (TNBC) is a difficult-to-treat, aggressive cancer type. TNBC is often associated with the cellular program of epithelial-mesenchymal transition (EMT) that confers drug resistance and metastasis. EMT and reverse mesenchymal-epithelial transition (MET) programs are regulated by several signaling pathways which converge on a group of transcription factors, EMT- TFs. Therapy approaches could rely on the EMT reversal to sensitise mesenchymal tumours to compounds effective against epithelial cancers. Here, we show that the antimalarial ROS-generating compound artesunate (ART) exhibits higher cytotoxicity in epithelial than mesenchymal breast cancer cell lines. Ectopic expression of EMT-TF ZEB1 in epithelial or ZEB1 depletion in mesenchymal cells, respectively, reduced or increased ART-generated ROS levels, DNA damage and apoptotic cell death. In epithelial cells, ZEB1 enhanced expression of superoxide dismutase 2 (SOD2) and glutathione peroxidase 8 (GPX8) implicated in ROS scavenging. Although SOD2 or GPX8 levels were unaffected in mesenchymal cells in response to ZEB1 depletion, stable ZEB1 knockdown enhanced total ROS. Receptor tyrosine kinase AXL maintains a mesenchymal phenotype and is overexpressed in TNBC. The clinically-relevant AXL inhibitor TP-0903 induced MET and synergised with ART to generate ROS, DNA damage and apoptosis in TNBC cells. TP-0903 reduced the expression of GPX8 and SOD2. Thus, TP-0903 and ZEB1 knockdown sensitised TNBC cells to ART, likely via different pathways. Synergistic interactions between TP-0903 and ART indicate that combination approaches involving these compounds can have therapeutic prospects for TNBC treatment.

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Section: Resultsmentioning

confidence: 99%

Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate

Terragno,

Vetrova,

Semenov

et al. 2024

Sci Rep

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“…This is derived from its aberrant signaling, leading to pathological settings, such as cancer and autoimmune diseases, among others [ 3 , 4 , 30 ]. For this reason, in recent years, medical research, especially tumor physiology research, has focused on the study of the Axl/Gas6 molecular axis, resulting in the development of different classes of therapeutic agents, from kinase inhibitors to anti-receptor antibodies and aptamers, even if no drug has been FDA-approved to date [ 16 , 17 ]. The binding of Gas6 to the extracellular portion of Axl triggers receptor dimerization, trans-phosphorylation, and activation.…”

Section: Discussionmentioning

confidence: 99%

“…They were not completely effective in blocking the Axl/Gas6 molecular axis, particularly in MET-amplified patients. However, clinical trials are currently in progress, and no drugs have been approved so far [ 16 , 17 ]. Thus, the challenge is to identify novel, specific, and active Axl targeting agents to be used as homing units in diagnostic applications or as therapeutic agents in single treatments or in combination with standard chemotherapy, overcoming the intrinsic limits of the molecules already developed and paving the way to increasingly personalized therapies.…”

Section: Introductionmentioning

confidence: 99%

Molecular Characterization of the Recombinant Ig1 Axl Receptor Domain: An Intriguing Bait for Screening in Drug Discovery

Di Stasi,

De Rosa,

Izzi

et al. 2024

Molecules

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Axl receptor tyrosine kinase and its ligand Gas6 regulate several biological processes and are involved in both the onset and progression of tumor malignancies and autoimmune diseases. Based on its key role in these settings, Axl is considered a promising target for the development of molecules with therapeutic and diagnostic purposes. In this paper, we describe the molecular characterization of the recombinant Ig1 domain of Axl (Ig1 Axl) and its biochemical properties. For the first time, an exhaustive spectroscopic characterization of the recombinant protein through circular dichroism and fluorescence studies is also reported, as well as a binding analysis to its natural ligand Gas6, paving the way for the use of recombinant Ig1 Axl as a bait in drug discovery screening procedures aimed at the identification of novel and specific binders targeting the Axl receptor.

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“…With the expanding role of AXL to the development of cancer, AXL has been identified as a promising candidate for novel targeted chemotherapeutic agents (61,85). No fewer than ten AXL receptor inhibitory compounds are under clinical investigation for the treatment of many cancers, including neuroendocrine-related tumor of the breast, ovary, and pancreas (86). These investigational agents include small molecule inhibitors, monoclonal antibodies, antibody-cytotoxic drug conjugates, CAR-T cell therapeutics, and soluble AXL receptor fusion proteins.…”

Section: Discussionmentioning

confidence: 99%

AXL/Gas6 signaling mechanisms in the hypothalamic-pituitary-gonadal axis

Mohammadzadeh

Amberg

2023

Front. Endocrinol.

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AXL is a receptor tyrosine kinase commonly associated with a variety of human cancers. Along with its ligand Gas6 (growth arrest-specific protein 6), AXL is emerging as an important regulator of neuroendocrine development and function. AXL signaling in response to Gas6 binding impacts neuroendocrine structure and function at the level of the brain, pituitary, and gonads. During development, AXL has been identified as an upstream inhibitor of gonadotropin receptor hormone (GnRH) production and also plays a key role in the migration of GnRH neurons from the olfactory placode to the forebrain. AXL is implicated in reproductive diseases including some forms of idiopathic hypogonadotropic hypogonadism and evidence suggests that AXL is required for normal spermatogenesis. Here, we highlight research describing AXL/Gas6 signaling mechanisms with a focus on the molecular pathways related to neuroendocrine function in health and disease. In doing so, we aim to present a concise account of known AXL/Gas6 signaling mechanisms to identify current knowledge gaps and inspire future research.

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AXL Inhibitors: Status of Clinical Development

Cited by 13 publications

References 64 publications

Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate

Mesenchymal–epithelial transition and AXL inhibitor TP-0903 sensitise triple-negative breast cancer cells to the antimalarial compound, artesunate

Molecular Characterization of the Recombinant Ig1 Axl Receptor Domain: An Intriguing Bait for Screening in Drug Discovery

AXL/Gas6 signaling mechanisms in the hypothalamic-pituitary-gonadal axis

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