AXL receptor tyrosine kinase

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Tyrosine-protein kinase receptor UFO is an enzyme that in humans is encoded by the AXL gene.[1][2] The gene was initially designated as UFO, in allusion to the unidentified function of this protein.[3] However, in the years since its discovery, research into AXL's expression profile and mechanism has made it an increasingly attractive target, especially for cancer therapeutics. In recent years, AXL has emerged as a key facilitator of immune escape and drug-resistance by cancer cells, leading to aggressive and metastatic cancers.[4]

AXL is a cell surface receptor tyrosine kinase, part of the TAM family of kinases including TYRO3 and MERTK.[5]

Gene and protein structure

The Axl gene is evolutionarily conserved between vertebrate species. This gene has two different alternatively spliced transcript variants.[2]

The protein encoded by this gene is a member of the receptor tyrosine kinase subfamily. Although it is similar to other receptor tyrosine kinases, the Axl protein represents a unique structure of the extracellular region that juxtaposes IgL and FNIII repeats.[2]

The AXL protein is characterized by an extracellular structure consisting of two fibronectin type 3-like repeats and two immunoglobulin-like repeats along with its intracellular tyrosine kinase domain.

Function

The AXL receptor transduces signals from the extracellular matrix into the cytoplasm by binding growth factors like vitamin K-dependent protein growth-arrest-specific gene 6 (GAS6). It is involved in the stimulation of cell proliferation and survival. Proteolytic cleavage of the AXL extracellular domain by the metalloproteinases ADAM10 and ADAM17 can downregulate this signalling activity.[6]

Signalling pathways activated downstream of AXL include PI3K-AKT-mTOR, MEKERK, NF-kB, and JAK/STAT.[7]

This receptor can also mediate cell aggregation by homophilic binding.[2]

AXL protein is expressed in normal tissues, particularly in bone marrow stroma and myeloid cells, and in tumour cells and tumour vasculature.[8][9] In cancer, AXL is expressed on the tumor cells as well as adjacent immune cells including dendritic cells, macrophages, and NK cells.

Axl is an inhibitor of the innate immune response. The function of activated AXL in normal tissues includes the efficient clearance of apoptotic material and the dampening of TLR-dependent inflammatory responses and natural killer cell activity.[10]

AXL is a putative driver of diverse cellular processes that are critical for the development, growth, and spread of tumours, including proliferation, invasiveness and migration, epithelial-to-mesenchymal transition, stemness, angiogenesis, and immune modulation.[7] AXL has been implicated as a cancer driver and correlated with poor survival in numeorus aggressive tumors including triple-negative breast cancer (TNBC), acute myeloid leukemia (AML), non-small-cell lung cancer (NSCLC), pancreatic cancer and ovarian cancer, among others.[11]

As a drug target

Axl was first isolated in 1988 and identified as an oncogene in a screen for transforming genes in patients with a chronic myelogenous leukemia- that progressed to 'blast crisis'.[12] Since then, increased AXL expression has been associated with numerous cancers including lung cancer, breast cancer, pancreatic cancer, ovarian cancer, colon cancer and melanoma among others, and shown to have a strong correlation with poor survival outcomes.

AXL has been shown to be a key driver of drug-resistance to targeted therapies, immuno therapies and chemotherapy in various animal models. Based on current knowledge of AXL’s role in therapy resistance, future studies will help to determine whether AXL has a translational application as a biomarker for predicting therapeutic response to established drugs.

Studies have shown that AXL knockdown leads to downregulation of transcription factors required for EMT, including Slug, Twist, and Zeb1, and to increased expression of E-cadherin.[13]

AXL is in close vicinity to the BCL3 oncogene, which is at 19q13.1-q13.2.[2]

AXL may also play an important role in Zika virus infection, allowing for entry of the virus into host cells.[14]

Clinical studies

Cancer

There is ongoing research to develop possible drugs to target this signalling pathway and treat cancers.[5]

Several drugs classified as "AXL inhibitors" have entered clinical trials; however, many target mutliple kinase receptors in addition to AXL. The most advanced AXL selective inhibitor is bemcentinib, BGB324 (previously R428), an oral small molecule currently in multiple Phase II clinical trials for NSCLC, TNBC, AML and melanoma. BGB324 is being pursued as monotherapy and as combination therapy with existing and emerging targeted therapies, immunotherapies and chemotherapy.

A monoclonal antibody targeting AXL (YW327.6S2) and an AXL decoy receptor (GL2I.T) are currently in preclinical development. Additionally, an oral AXL inhibitor (TP-0903) is expected to enter Phase 1 clinical trial in November 2016 (in advanced solid tumours: NCT02729298).

Non-selective Axl inhibitors in clinical trials included:[5]:Table 2 LY2801653, MP-470 (Amuvatinib), SKI-606 (Bosutinib), MGCD 265, ASP2215, XL184 (Cabozantinib), GSK1363089/XL880 (Foretinib), and SGI-7079.

e.g. Astellas Pharma is currently testing ASP2215 (Gilteritinib), a dual FLT3-AXL tyrosine kinase inhibitor in acute myeloid leukemia (AML).[5] In 2017 Gilteritinib gained FDA Orphan drug status for AML.[15]

These approved drugs and ongoing and pending clinical trials highlight the potentially wide-ranging safety and efficacy of AXL inhibition.[7]

Interactions

AXL receptor tyrosine kinase has been shown to interact with TENC1.[16]

References

  1. ↑ O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R, Le Beau MM, Earp HS, Liu ET (Oct 1991). "axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase". Molecular and Cellular Biology. 11 (10): 5016–31. PMC 361494. PMID 1656220.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Entrez Gene: AXL AXL receptor tyrosine kinase".
  3. ↑ Janssen JW, Schulz AS, Steenvoorden AC, Schmidberger M, Strehl S, Ambros PF, Bartram CR (1991). "A novel putative tyrosine kinase receptor with oncogenic potential". Oncogene. 6 (11): 2113–20. PMID 1834974.
  4. ↑ Davidsen, Kjersti T.; Haaland, Gry S.; Lie, Maria K.; Lorens, James B. (2017). The Role of Axl Receptor Tyrosine Kinase in Tumor Cell Plasticity and Therapy Resistance. In: Akslen L., Watnick R. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. pp. 351–376. ISBN 978-3-319-39147-2.
  5. ↑ 5.0 5.1 5.2 5.3 Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B (2014). "AXL kinase as a novel target for cancer therapy". Oncotarget. 5 (20): 9546–63. doi:10.18632/oncotarget.2542. PMC 4259419. PMID 25337673.
  6. ↑ Miller MA, Oudin MJ, Sullivan RJ, Wang SJ, Meyer AS, Im H, Frederick DT, Tadros J, Griffith LG, Lee H, Weissleder R, Flaherty KT, Gertler FB, Lauffenburger DA (2016). "Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance". Cancer Discovery. 6 (4): 382–99. doi:10.1158/2159-8290.CD-15-0933. PMID 26984351.
  7. ↑ 7.0 7.1 7.2 Gay, CM; et al. (2016). "Giving AXL the axe: targeting AXL in human malignancy". British Journal of Cancer. 116: 415–423 – via Springer Nature.
  8. ↑ Neubauer A, Fiebeler A, Graham DK, O’Bryan JP, Schmidt CA, Barckow P, Serke S, Siegert W, Snodgrass HR, Huhn D, Liu ET (1994) Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis. Blood 84(6): 1931–1941.
  9. ↑ Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW (2005) Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia 7(12): 1058–1064.
  10. ↑ Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131(6): 1124–1136.
  11. ↑ Vajkoczy P, Knyazev P, Kunkel A, Capelle HH, Behrndt S, von Tengg-Kobligk H, Kiessling F, Eichelsbacher U, Essig M, Read TA, Erber R, Ullrich A (Apr 2006). "Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival". Proceedings of the National Academy of Sciences of the United States of America. 103 (15): 5799–804. doi:10.1073/pnas.0510923103. PMC 1458653. PMID 16585512.
  12. ↑ Liu E, Hjelle B, Bishop JM (1988) Transforming genes in chronic myelogenous leukemia. Proc Natl Acad Sci USA 85(6): 1952–1956.
  13. ↑ Asiedu MK, Beauchamp-Perez FD, Ingle JN, Behrens MD, Radisky DC, Knutson KL (2014) AXL induces epithelial-to mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene 33(10):1316–1324.
  14. ↑ Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR (2016). "Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells". Cell Stem Cell. 18 (5): 591–596. doi:10.1016/j.stem.2016.03.012. ISSN 1934-5909. PMID 27038591.
  15. ↑ Gilteritinib Granted Orphan Drug Status for Acute Myeloid Leukemia. 2017
  16. ↑ Hafizi S, Alindri F, Karlsson R, Dahlbäck B (Dec 2002). "Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin". Biochemical and Biophysical Research Communications. 299 (5): 793–800. doi:10.1016/S0006-291X(02)02718-3. PMID 12470648.

Further reading

  • Neubauer A, Burchert A, Maiwald C, Gruss HJ, Serke S, Huhn D, Wittig B, Liu E (Mar 1997). "Recent progress on the role of Axl, a receptor tyrosine kinase, in malignant transformation of myeloid leukemias". Leukemia & Lymphoma. 25 (1–2): 91–6. doi:10.3109/10428199709042499. PMID 9130617.
  • Bergsagel PL, Victor-Kobrin C, Timblin CR, Trepel J, Kuehl WM (Jan 1992). "A murine cDNA encodes a pan-epithelial glycoprotein that is also expressed on plasma cells". Journal of Immunology. 148 (2): 590–6. PMID 1729376.
  • Partanen J, Mäkelä TP, Alitalo R, Lehväslaiho H, Alitalo K (Nov 1990). "Putative tyrosine kinases expressed in K-562 human leukemia cells". Proceedings of the National Academy of Sciences of the United States of America. 87 (22): 8913–7. doi:10.1073/pnas.87.22.8913. PMC 55070. PMID 2247464.
  • Neubauer A, Fiebeler A, Graham DK, O'Bryan JP, Schmidt CA, Barckow P, Serke S, Siegert W, Snodgrass HR, Huhn D (Sep 1994). "Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis". Blood. 84 (6): 1931–41. PMID 7521695.
  • O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET (Jan 1995). "The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage". The Journal of Biological Chemistry. 270 (2): 551–7. doi:10.1074/jbc.270.2.551. PMID 7822279.
  • Lee ST, Strunk KM, Spritz RA (Dec 1993). "A survey of protein tyrosine kinase mRNAs expressed in normal human melanocytes". Oncogene. 8 (12): 3403–10. PMID 8247543.
  • Schulz AS, Schleithoff L, Faust M, Bartram CR, Janssen JW (Feb 1993). "The genomic structure of the human UFO receptor". Oncogene. 8 (2): 509–13. PMID 8381225.
  • O'Bryan JP, Songyang Z, Cantley L, Der CJ, Pawson T (Apr 1996). "A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain". Proceedings of the National Academy of Sciences of the United States of America. 93 (7): 2729–34. doi:10.1073/pnas.93.7.2729. PMC 39699. PMID 8610109.
  • Mark MR, Chen J, Hammonds RG, Sadick M, Godowsk PJ (Apr 1996). "Characterization of Gas6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and Axl". The Journal of Biological Chemistry. 271 (16): 9785–9. doi:10.1074/jbc.271.16.9785. PMID 8621659.
  • Braunger J, Schleithoff L, Schulz AS, Kessler H, Lammers R, Ullrich A, Bartram CR, Janssen JW (Jun 1997). "Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site". Oncogene. 14 (22): 2619–31. doi:10.1038/sj.onc.1201123. PMID 9178760.
  • Tanaka K, Nagayama Y, Nakano T, Takamura N, Namba H, Fukada S, Kuma K, Yamashita S, Niwa M (Mar 1998). "Expression profile of receptor-type protein tyrosine kinase genes in the human thyroid". Endocrinology. 139 (3): 852–8. doi:10.1210/en.139.3.852. PMID 9492013.
  • Yanagita M, Arai H, Ishii K, Nakano T, Ohashi K, Mizuno K, Varnum B, Fukatsu A, Doi T, Kita T (Apr 2001). "Gas6 regulates mesangial cell proliferation through Axl in experimental glomerulonephritis". The American Journal of Pathology. 158 (4): 1423–32. doi:10.1016/S0002-9440(10)64093-X. PMC 1891897. PMID 11290560.
  • Sun WS, Misao R, Iwagaki S, Fujimoto J, Tamaya T (Jun 2002). "Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases, Axl and Sky, in human uterine endometrium and ovarian endometriosis". Molecular Human Reproduction. 8 (6): 552–8. doi:10.1093/molehr/8.6.552. PMID 12029073.
  • D'Arcangelo D, Gaetano C, Capogrossi MC (Oct 2002). "Acidification prevents endothelial cell apoptosis by Axl activation". Circulation Research. 91 (7): e4–12. doi:10.1161/01.RES.0000036753.50601.E9. PMID 12364394.
  • Hafizi S, Alindri F, Karlsson R, Dahlbäck B (Dec 2002). "Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin". Biochemical and Biophysical Research Communications. 299 (5): 793–800. doi:10.1016/S0006-291X(02)02718-3. PMID 12470648.
  • Ito M, Nakashima M, Nakayama T, Ohtsuru A, Nagayama Y, Takamura N, Demedchik EP, Sekine I, Yamashita S (Nov 2002). "Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl". Thyroid. 12 (11): 971–5. doi:10.1089/105072502320908303. PMID 12490074.

External links

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