Targeting Axl and Mer Kinases in Cancer

Receptor tyrosine kinases (RTK) are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play an important role in signal transduction in both normal and malignant cells. The mammalian TAM RTK family includes 3 closely related members: Tyro-3, Axl, and Mer. Overexpression or ectopic expression of the TAM receptors has been detected in a wide array of human cancers. Growth arrest-specific gene 6 has been identified as the major ligand for these TAM RTKs, and its binding to the receptors has been shown to promote proliferation and survival of cancer cells in vitro. Abnormal expression and activation of Axl or Mer can provide a survival advantage for certain cancer cells. Inhibition of Axl and Mer may enhance the sensitivity of cancer cells to cytotoxic agents and would potentially be a therapeutic strategy to target cancer cells. This review elucidates the role of Axl and Mer in normal cellular function and their role in oncogenesis. In addition, we review the potential to inhibit these RTKs for the development of therapeutic targets in treatment of cancer. Mol Cancer Ther; 10(10); 1763–73. ©2011 AACR.

[1]  Douglas B. Evans,et al.  Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma , 2011, Cancer.

[2]  Wei Li,et al.  Tubby and tubby‐like protein 1 are new MerTK ligands for phagocytosis , 2010, The EMBO journal.

[3]  E. Montgomery,et al.  The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma , 2010, Cancer biology & therapy.

[4]  Guang Yang,et al.  Differential expression of Axl in hepatocellular carcinoma and correlation with tumor lymphatic metastasis , 2010, Molecular carcinogenesis.

[5]  Kevin Wei,et al.  AXL is an essential factor and therapeutic target for metastatic ovarian cancer. , 2010, Cancer research.

[6]  R. Weimer,et al.  An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies , 2010, Oncogene.

[7]  H. Earp,et al.  Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors , 2010, Expert opinion on therapeutic targets.

[8]  A. Tulpule,et al.  Induction, regulation, and biologic function of Axl receptor tyrosine kinase in Kaposi sarcoma. , 2010, Blood.

[9]  A. Thorburn,et al.  Inhibition of Mer and Axl Receptor Tyrosine Kinases in Astrocytoma Cells Leads to Increased Apoptosis and Improved Chemosensitivity , 2010, Molecular Cancer Therapeutics.

[10]  Y. Hitoshi,et al.  R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. , 2010, Cancer research.

[11]  Bjørn Tore Gjertsen,et al.  Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival , 2009, Proceedings of the National Academy of Sciences.

[12]  D. Bearss,et al.  Targeting Axl Kinase in Hematological Malignancies. , 2009 .

[13]  J. Zha,et al.  Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis , 2009, Oncogene.

[14]  Kristen M. Jacobsen,et al.  Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia. , 2009, Blood.

[15]  Joel Greshock,et al.  Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. , 2009, Cancer research.

[16]  B. Dahlbäck,et al.  Differential Expression of Axl and Gas6 in Renal Cell Carcinoma Reflecting Tumor Advancement and Survival , 2009, Clinical Cancer Research.

[17]  G. Feldmann,et al.  The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target , 2009, Cancer biology & therapy.

[18]  Xudong Huang,et al.  Structural insights into the inhibited states of the Mer receptor tyrosine kinase , 2009, Journal of structural biology.

[19]  Ming-Tseh Lin,et al.  Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. , 2008, Cancer letters.

[20]  K. Tai,et al.  Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-κB and Brg-1 , 2008, Oncogene.

[21]  G. Lemke,et al.  Immunobiology of the TAM receptors , 2008, Nature Reviews Immunology.

[22]  László Orfi,et al.  AXL is a potential target for therapeutic intervention in breast cancer progression. , 2008, Cancer research.

[23]  M. Kerin,et al.  Growth arrest-specific gene 6 expression in human breast cancer , 2008, British Journal of Cancer.

[24]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[25]  A. Ullrich,et al.  Axl and Growth Arrest–Specific Gene 6 Are Frequently Overexpressed in Human Gliomas and Predict Poor Prognosis in Patients with Glioblastoma Multiforme , 2008, Clinical Cancer Research.

[26]  H. Garewal,et al.  A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors , 2007, Oncogene.

[27]  K. Heidenreich,et al.  Adhesion-related kinase induction of migration requires phosphatidylinositol-3-kinase and ras stimulation of rac activity in immortalized gonadotropin-releasing hormone neuronal cells. , 2007, Endocrinology.

[28]  B. Varnum,et al.  A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. , 2007, Blood.

[29]  D. Bearss,et al.  413 POSTER Discovery and characterization of a series of Axl kinase inhibitors using the CLIMB process , 2006 .

[30]  H. Snodgrass,et al.  Ectopic Expression of the Proto-oncogene Mer in Pediatric T-Cell Acute Lymphoblastic Leukemia , 2006, Clinical Cancer Research.

[31]  M. Essig,et al.  Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[32]  R. Timpl,et al.  Structural basis for Gas6–Axl signalling , 2006, The EMBO journal.

[33]  Y. Chu,et al.  Expression of axl in lung adenocarcinoma and correlation with tumor progression. , 2005, Neoplasia.

[34]  James L Mohler,et al.  Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. , 2005, Cancer research.

[35]  D. Hartmann,et al.  Associates with Gas6 in Mouse Serum Adam10-dependent Cleavage and Soluble Axl Is Generated by Supplemental Material , 2005 .

[36]  Stephen T. C. Wong,et al.  Multiple roles for the receptor tyrosine kinase axl in tumor formation. , 2005, Cancer research.

[37]  L. Castello,et al.  Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor , 2005, Journal of cellular physiology.

[38]  R. Birge,et al.  A role for Mer tyrosine kinase in αvβ5 integrin-mediated phagocytosis of apoptotic cells , 2005, Journal of Cell Science.

[39]  H. Kung,et al.  Signal Pathways in Up-regulation of Chemokines by Tyrosine Kinase MER/NYK in Prostate Cancer Cells , 2004, Cancer Research.

[40]  M. Blostein,et al.  Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells. , 2004, American journal of physiology. Heart and circulatory physiology.

[41]  B. Dahlbäck,et al.  Vitamin K-dependent Gas6 activates ERK kinase and stimulates growth of cardiac fibroblasts. , 2004, Biochemical and biophysical research communications.

[42]  T. Tamaya,et al.  Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers. , 2003, Annals of oncology : official journal of the European Society for Medical Oncology.

[43]  M. Ehinger,et al.  Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. , 2002, Cancer research.

[44]  Toshikazu Nakamura,et al.  Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons , 2002, Journal of neuroscience research.

[45]  C. Chi,et al.  Clinical significance of AXL kinase family in gastric cancer. , 2002, Anticancer research.

[46]  F. Meric,et al.  Expression profile of tyrosine kinases in breast cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[47]  R. Hansen,et al.  MCF-10A-NeoST: a new cell system for studying cell-ECM and cell-cell interactions in breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[48]  D. Brat,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Novel Patterns of Gene Expression in Pituitary Adenomas Identified by Complementary Deoxyribonucleic Acid Microarrays and Quantitative , 2000 .

[49]  E. Dreher,et al.  Estrogen dependent expression of the receptor tyrosine kinase axl in normal and malignant human breast. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[50]  P. Carmeliet,et al.  Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis , 2001, Nature Medicine.

[51]  R. Herrmann,et al.  Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK) , 1999, Leukemia.

[52]  S. Yamashita,et al.  Expression of the Axl receptor tyrosine kinase in human thyroid carcinoma. , 1999, Thyroid : official journal of the American Thyroid Association.

[53]  H. Weier,et al.  Assignment1 of protooncogene MERTK (a.k.a. c-mer) to human chromosome 2q14.1 by in situ hybridization , 1999, Cytogenetic and Genome Research.

[54]  J. McCarty,et al.  The Nck SH2/SH3 adaptor protein: a regulator of multiple intracellular signal transduction events , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.

[55]  S. Tsai,et al.  Parallel hybridization analysis of multiple protein kinase genes: identification of gene expression patterns characteristic of human hepatocellular carcinoma. , 1998, Genomics.

[56]  E. Attar,et al.  GAS6 Induces Axl-mediated Chemotaxis of Vascular Smooth Muscle Cells* , 1998, The Journal of Biological Chemistry.

[57]  B. Varnum,et al.  GAS6 Mediates Adhesion of Cells Expressing the Receptor Tyrosine Kinase Axl* , 1997, The Journal of Biological Chemistry.

[58]  E. Ruaro,et al.  Requirement of phosphatidylinositol 3-kinase-dependent pathway and Src for Gas6-Axl mitogenic and survival activities in NIH 3T3 fibroblasts , 1997, Molecular and cellular biology.

[59]  A. Ullrich,et al.  Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site , 1997, Oncogene.

[60]  E. Liu,et al.  Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase , 1996, Molecular and cellular biology.

[61]  H. Snodgrass,et al.  Cloning and developmental expression analysis of the murine c-mer tyrosine kinase. , 1995, Oncogene.

[62]  E. Liu,et al.  Receptor tyrosine kinases expressed in metastatic colon cancer , 1995, International journal of cancer.

[63]  Pamela F. Jones,et al.  The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptor tyrosine kinases , 1995, Cell.

[64]  M. Herlyn,et al.  Protein kinases in normal and transformed melanocytes , 1994, Melanoma research.

[65]  D. Huhn,et al.  Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis. , 1994, Blood.

[66]  H. Snodgrass,et al.  Cloning and Mrna Expression Analysis of a Novel Human Protooncogene, C-merr , 2022 .

[67]  H. Hanafusa,et al.  The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/GN-III domains. , 1994, The Journal of biological chemistry.

[68]  R. Espinosa,et al.  axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase , 1991, Molecular and cellular biology.

[69]  H. Earp,et al.  TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. , 2008, Advances in cancer research.

[70]  R. Birge,et al.  A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. , 2005, Journal of cell science.

[71]  J. Yokota,et al.  Biological properties and gene expression associated with metastatic potential of human osteosarcoma , 2004, Clinical & Experimental Metastasis.

[72]  B. Varnum,et al.  Mer Receptor Tyrosine Kinase Signaling PREVENTION OF APOPTOSIS AND ALTERATION OF CYTOSKELETAL ARCHITECTURE WITHOUT STIMULATION OR PROLIFERATION* , 2002 .

[73]  A. Kraus,et al.  Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion. , 2001, European journal of cancer.

[74]  K. Hirokawa,et al.  Overexpression of protein tyrosine kinases in human esophageal cancer. , 1997, Pathobiology : journal of immunopathology, molecular and cellular biology.

[75]  F. Behm,et al.  Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study. , 1990, Blood.