AXL receptor tyrosine kinase: Difference between revisions

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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.
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.
AXL is in close vicinity to the [[BCL3]] oncogene, which is at 19q13.1-q13.2.<ref name="entrez" />


==Function ==
==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|cell proliferation and survival]]. Proteolytic cleavage of the AXL extracellular domain by the [[metalloproteinases]] [[ADAM10]] and [[ADAM17]] can downregulate this signalling activity.<ref name="pmid26984351">{{cite journal |doi =10.1158/2159-8290.CD-15-0933 |pmid=26984351 |title= Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance |journal=Cancer Discovery |volume=6 |issue=4|pages= 382-99 |year=2016 | vauthors = 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}}</ref>
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|cell proliferation and survival]]. Proteolytic cleavage of the AXL extracellular domain by the [[metalloproteinases]] [[ADAM10]] and [[ADAM17]] can downregulate this signalling activity.<ref name="pmid26984351">{{cite journal |doi =10.1158/2159-8290.CD-15-0933 |pmid=26984351 |title= Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance |journal=Cancer Discovery |volume=6 |issue=4|pages= 382-99 |year=2016 | vauthors = 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 |pmc=5087317}}</ref>
 
Signalling pathways activated downstream of AXL include PI3K-AKT-mTOR, MEKERK, NF-kB, and JAK/STAT.<ref name="GayBalaji2017">{{cite journal|last1=Gay|first1=Carl M|last2=Balaji|first2=Kavitha|last3=Byers|first3=Lauren Averett|title=Giving AXL the axe: targeting AXL in human malignancy|journal=British Journal of Cancer|volume=116|issue=4|year=2017|pages=415–423|issn=0007-0920|doi=10.1038/bjc.2016.428|pmc=5318970}}</ref>


Signalling pathways activated downstream of AXL include PI3K-AKT-mTOR, MEKERK, NF-kB, and JAK/STAT.<ref name=":0">{{Cite journal|last=Gay|first=CM, et al.|date=2016|title=Giving AXL the axe: targeting AXL in human malignancy|url=|journal=British Journal of Cancer|volume=116|pages=415–423|via=Springer Nature}}</ref>


This receptor can also mediate cell aggregation by homophilic binding.<ref name="entrez"/>
This receptor can also mediate cell aggregation by homophilic binding.<ref name="entrez"/>


AXL protein is expressed in normal tissues, particularly in bone marrow stroma and myeloid cells, and in tumour cells and tumour vasculature.<ref>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.</ref><ref>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.</ref> In cancer, AXL is expressed on the tumor cells as well as adjacent immune cells including [[dendritic cell]]s, [[macrophage]]s, and [[Natural killer cell|NK cells]].
AXL protein is expressed in normal tissues, particularly in bone marrow stroma and myeloid cells, and in tumour cells and tumour vasculature.<ref name="pmid7521695">{{cite journal |vauthors = Neubauer A, Fiebeler A, Graham DK, O'Bryan JP, Schmidt CA, Barckow P, Serke S, Siegert W, Snodgrass HR, Huhn D |title = Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis |journal = Blood |volume = 84 |issue = 6 |pages = 1931–41 |year = 1994 |pmid = 7521695 }}</ref><ref name=Shieh2005>{{cite journal |vauthors = Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW |title = Expression of axl in lung adenocarcinoma and correlation with tumor progression |journal = Neoplasia |volume = 7 |issue = 12 |pages = 1058–64 |year = 2005 |pmid = 16354588 |pmc = 1501169 |doi=10.1593/neo.05640}}</ref> In cancer, AXL is expressed on the tumor cells as well as adjacent immune cells including [[dendritic cell]]s, [[macrophage]]s, and [[Natural killer cell|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.<ref>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.</ref>
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.<ref name="pmid18083102">{{cite journal |vauthors = Rothlin CV, Ghosh S, Zuniga EI, Oldstone MB, Lemke G |title = TAM receptors are pleiotropic inhibitors of the innate immune response |journal = Cell |volume = 131 |issue = 6 |pages = 1124–36 |year = 2007 |pmid = 18083102 |doi = 10.1016/j.cell.2007.10.034}}</ref>


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.<ref name=":0" /> 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.<ref name="pmid16585512">{{cite journal | vauthors = 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 | title = Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 15 | pages = 5799–804 | date = Apr 2006 | pmid = 16585512 | pmc = 1458653 | doi = 10.1073/pnas.0510923103 }}</ref>
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.<ref name="GayBalaji2017"/> 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.<ref name="pmid16585512">{{cite journal | vauthors = 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 | title = Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 15 | pages = 5799–804 | date = Apr 2006 | pmid = 16585512 | pmc = 1458653 | doi = 10.1073/pnas.0510923103 }}</ref>


== As a drug target ==
==Clinical significance==
 
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'.<ref name="pmid3279421">{{cite journal |vauthors = Liu E, Hjelle B, Bishop JM |title = Transforming genes in chronic myelogenous leukemia |journal = Proc. Natl. Acad. Sci. U.S.A. |volume = 85 |issue = 6 |pages = 1952–6 |year = 1988 |pmid = 3279421 |pmc = 279899 |doi=10.1073/pnas.85.6.1952}}</ref>  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.<ref name=Shieh2005/>
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'.<ref>Liu E, Hjelle B, Bishop JM (1988) Transforming genes in chronic myelogenous leukemia. Proc Natl Acad Sci USA 85(6): 1952–1956.</ref>  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.
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.<ref>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.</ref>
AXL is in close vicinity to the [[BCL3]] oncogene, which is at 19q13.1-q13.2.<ref name="entrez" />


AXL may also play an important role in [[Zika virus]] infection, allowing for entry of the virus into host cells.<ref>{{Cite journal
AXL may also play an important role in [[Zika virus]] infection, allowing for entry of the virus into host cells.<ref>{{Cite journal
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  | pmid=27038591
  | pmid=27038591
}}</ref>
}}</ref>
== As a drug target ==
Studies have shown that AXL knockdown leads to downregulation of transcription factors required for [[epithelial-to-mesenchymal transition|EMT]], including Slug, Twist, and Zeb1, and to increased expression of E-cadherin.<ref name=Aisedu2014>{{cite journal |vauthors = Asiedu MK, Beauchamp-Perez FD, Ingle JN, Behrens MD, Radisky DC, Knutson KL |title = AXL induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells |journal = Oncogene |volume = 33 |issue = 10 |pages = 1316–24 |year = 2014 |pmid = 23474758 |pmc = 3994701 |doi = 10.1038/onc.2013.57}}</ref>
There is ongoing research to develop possible drugs to target this signalling pathway and treat cancers.<ref name="pmid25337673">{{cite journal | vauthors = Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B | title = AXL kinase as a novel target for cancer therapy | journal = Oncotarget | volume = 5 | issue = 20 | pages = 9546–63 | year = 2014 | pmid = 25337673 | pmc = 4259419 | url =  http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=2542 | doi=10.18632/oncotarget.2542}}</ref>


==Clinical studies==
==Clinical studies==


===Cancer===
===Cancer===
There is ongoing research to develop possible drugs to target this signalling pathway and treat cancers.<ref name="pmid25337673">{{cite journal | vauthors = Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B | title = AXL kinase as a novel target for cancer therapy | journal = Oncotarget | volume = 5 | issue = 20 | pages = 9546–63 | year = 2014 | pmid = 25337673 | pmc = 4259419 | url =  http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=2542 | doi=10.18632/oncotarget.2542}}</ref>


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.
Several drugs classified as "AXL inhibitors" have entered clinical trials; however, many target multiple kinase receptors in addition to AXL. The most advanced AXL ''selective'' inhibitor is [[bemcentinib]] (BGB324 or R428), an oral small molecule currently in multiple Phase II clinical trials for NSCLC, TNBC, AML and melanoma. Bemcentinib 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).
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:<ref name="pmid25337673" />{{rp|Table 2}} LY2801653, MP-470 ([[Amuvatinib]]), SKI-606 ([[Bosutinib]]), MGCD 265, ASP2215, XL184 ([[Cabozantinib]]), GSK1363089/XL880 ([[Foretinib]]), and SGI-7079.
Non-selective AXL inhibitors in clinical trials included:<ref name="pmid25337673" />{{rp|Table 2}} LY2801653, [[amuvatinib]] (MP-470), [[bosutinib]] (SKI-606), MGCD 265, ASP2215, [[cabozantinib]] (XL184), [[foretinib]] (GSK1363089/XL880), and SGI-7079.


e.g. [[Astellas Pharma]] is currently testing ASP2215 ([[Gilteritinib]]), a dual [[FLT3]]-AXL tyrosine kinase inhibitor in [[acute myeloid leukemia]] (AML).<ref name="pmid25337673"/> In 2017 Gilteritinib gained FDA [[Orphan drug status]] for AML.<ref>[http://www.cancertherapyadvisor.com/hematologic-cancers/acute-leukemia-aml-gilteritinib-fda-orphan-drug-status/article/676474/ Gilteritinib Granted Orphan Drug Status for Acute Myeloid Leukemia. 2017]</ref>
[[Astellas Pharma]] is currently testing [[gilteritinib]] (ASP2215), a dual [[FLT3]]-AXL tyrosine kinase inhibitor in [[acute myeloid leukemia]] (AML).<ref name="pmid25337673"/> In 2017, gilteritinib gained FDA [[orphan drug status]] for AML.<ref>{{cite web |url=http://www.cancertherapyadvisor.com/hematologic-cancers/acute-leukemia-aml-gilteritinib-fda-orphan-drug-status/article/676474/|title= Gilteritinib Granted Orphan Drug Status for Acute Myeloid Leukemia |last=Nam |first=James |date=July 20, 2017 |website=Cancer Therapy Advisor |publisher=Haymarket Media Inc |access-date= }}</ref>


These approved drugs and ongoing and pending clinical trials highlight the potentially wide-ranging safety and efficacy of AXL inhibition.<ref name=":0" />
These approved drugs and ongoing and pending clinical trials highlight the potentially wide-ranging safety and efficacy of AXL inhibition.<ref name="GayBalaji2017"/>


== Interactions ==
== Interactions ==
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== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Neubauer A, Burchert A, Maiwald C, Gruss HJ, Serke S, Huhn D, Wittig B, Liu E | title = Recent progress on the role of Axl, a receptor tyrosine kinase, in malignant transformation of myeloid leukemias | journal = Leukemia & Lymphoma | volume = 25 | issue = 1-2 | pages = 91–6 | date = Mar 1997 | pmid = 9130617 | doi = 10.3109/10428199709042499 }}
* {{cite journal | vauthors = Neubauer A, Burchert A, Maiwald C, Gruss HJ, Serke S, Huhn D, Wittig B, Liu E | title = Recent progress on the role of Axl, a receptor tyrosine kinase, in malignant transformation of myeloid leukemias | journal = Leukemia & Lymphoma | volume = 25 | issue = 1–2 | pages = 91–6 | date = Mar 1997 | pmid = 9130617 | doi = 10.3109/10428199709042499 }}
* {{cite journal | vauthors = Bergsagel PL, Victor-Kobrin C, Timblin CR, Trepel J, Kuehl WM | title = A murine cDNA encodes a pan-epithelial glycoprotein that is also expressed on plasma cells | journal = Journal of Immunology | volume = 148 | issue = 2 | pages = 590–6 | date = Jan 1992 | pmid = 1729376 | doi =  }}
* {{cite journal | vauthors = Bergsagel PL, Victor-Kobrin C, Timblin CR, Trepel J, Kuehl WM | title = A murine cDNA encodes a pan-epithelial glycoprotein that is also expressed on plasma cells | journal = Journal of Immunology | volume = 148 | issue = 2 | pages = 590–6 | date = Jan 1992 | pmid = 1729376 | doi =  }}
* {{cite journal | vauthors = Partanen J, Mäkelä TP, Alitalo R, Lehväslaiho H, Alitalo K | title = Putative tyrosine kinases expressed in K-562 human leukemia cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 22 | pages = 8913–7 | date = Nov 1990 | pmid = 2247464 | pmc = 55070 | doi = 10.1073/pnas.87.22.8913 }}
* {{cite journal | vauthors = Partanen J, Mäkelä TP, Alitalo R, Lehväslaiho H, Alitalo K | title = Putative tyrosine kinases expressed in K-562 human leukemia cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 22 | pages = 8913–7 | date = Nov 1990 | pmid = 2247464 | pmc = 55070 | doi = 10.1073/pnas.87.22.8913 }}
* {{cite journal | vauthors = Neubauer A, Fiebeler A, Graham DK, O'Bryan JP, Schmidt CA, Barckow P, Serke S, Siegert W, Snodgrass HR, Huhn D | title = Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis | journal = Blood | volume = 84 | issue = 6 | pages = 1931–41 | date = Sep 1994 | pmid = 7521695 | doi =  }}
* {{cite journal | vauthors = O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET | title = The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage | journal = The Journal of Biological Chemistry | volume = 270 | issue = 2 | pages = 551–7 | date = Jan 1995 | pmid = 7822279 | doi = 10.1074/jbc.270.2.551 }}
* {{cite journal | vauthors = O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET | title = The transforming receptor tyrosine kinase, Axl, is post-translationally regulated by proteolytic cleavage | journal = The Journal of Biological Chemistry | volume = 270 | issue = 2 | pages = 551–7 | date = Jan 1995 | pmid = 7822279 | doi = 10.1074/jbc.270.2.551 }}
* {{cite journal | vauthors = Lee ST, Strunk KM, Spritz RA | title = A survey of protein tyrosine kinase mRNAs expressed in normal human melanocytes | journal = Oncogene | volume = 8 | issue = 12 | pages = 3403–10 | date = Dec 1993 | pmid = 8247543 | doi =  }}
* {{cite journal | vauthors = Lee ST, Strunk KM, Spritz RA | title = A survey of protein tyrosine kinase mRNAs expressed in normal human melanocytes | journal = Oncogene | volume = 8 | issue = 12 | pages = 3403–10 | date = Dec 1993 | pmid = 8247543 | doi =  }}
Line 87: Line 88:
* {{cite journal | vauthors = Sun WS, Misao R, Iwagaki S, Fujimoto J, Tamaya T | title = Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases, Axl and Sky, in human uterine endometrium and ovarian endometriosis | journal = Molecular Human Reproduction | volume = 8 | issue = 6 | pages = 552–8 | date = Jun 2002 | pmid = 12029073 | doi = 10.1093/molehr/8.6.552 }}
* {{cite journal | vauthors = Sun WS, Misao R, Iwagaki S, Fujimoto J, Tamaya T | title = Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases, Axl and Sky, in human uterine endometrium and ovarian endometriosis | journal = Molecular Human Reproduction | volume = 8 | issue = 6 | pages = 552–8 | date = Jun 2002 | pmid = 12029073 | doi = 10.1093/molehr/8.6.552 }}
* {{cite journal | vauthors = D'Arcangelo D, Gaetano C, Capogrossi MC | title = Acidification prevents endothelial cell apoptosis by Axl activation | journal = Circulation Research | volume = 91 | issue = 7 | pages = e4-12 | date = Oct 2002 | pmid = 12364394 | doi = 10.1161/01.RES.0000036753.50601.E9 }}
* {{cite journal | vauthors = D'Arcangelo D, Gaetano C, Capogrossi MC | title = Acidification prevents endothelial cell apoptosis by Axl activation | journal = Circulation Research | volume = 91 | issue = 7 | pages = e4-12 | date = Oct 2002 | pmid = 12364394 | doi = 10.1161/01.RES.0000036753.50601.E9 }}
* {{cite journal | vauthors = Hafizi S, Alindri F, Karlsson R, Dahlbäck B | title = Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin | journal = Biochemical and Biophysical Research Communications | volume = 299 | issue = 5 | pages = 793–800 | date = Dec 2002 | pmid = 12470648 | doi = 10.1016/S0006-291X(02)02718-3 }}
* {{cite journal | vauthors = Ito M, Nakashima M, Nakayama T, Ohtsuru A, Nagayama Y, Takamura N, Demedchik EP, Sekine I, Yamashita S | title = Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl | journal = Thyroid | volume = 12 | issue = 11 | pages = 971–5 | date = Nov 2002 | pmid = 12490074 | doi = 10.1089/105072502320908303 }}
* {{cite journal | vauthors = Ito M, Nakashima M, Nakayama T, Ohtsuru A, Nagayama Y, Takamura N, Demedchik EP, Sekine I, Yamashita S | title = Expression of receptor-type tyrosine kinase, Axl, and its ligand, Gas6, in pediatric thyroid carcinomas around chernobyl | journal = Thyroid | volume = 12 | issue = 11 | pages = 971–5 | date = Nov 2002 | pmid = 12490074 | doi = 10.1089/105072502320908303 }}
{{refend}}
{{refend}}

Latest revision as of 01:01, 12 May 2018

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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.

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

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]

Clinical significance

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.[9]

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.

AXL may also play an important role in Zika virus infection, allowing for entry of the virus into host cells.[13]

As a drug target

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.[14]

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

Clinical studies

Cancer

Several drugs classified as "AXL inhibitors" have entered clinical trials; however, many target multiple kinase receptors in addition to AXL. The most advanced AXL selective inhibitor is bemcentinib (BGB324 or R428), an oral small molecule currently in multiple Phase II clinical trials for NSCLC, TNBC, AML and melanoma. Bemcentinib 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, amuvatinib (MP-470), bosutinib (SKI-606), MGCD 265, ASP2215, cabozantinib (XL184), foretinib (GSK1363089/XL880), and SGI-7079.

Astellas Pharma is currently testing gilteritinib (ASP2215), 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. PMC 5087317. PMID 26984351.
  7. ↑ 7.0 7.1 7.2 Gay, Carl M; Balaji, Kavitha; Byers, Lauren Averett (2017). "Giving AXL the axe: targeting AXL in human malignancy". British Journal of Cancer. 116 (4): 415–423. doi:10.1038/bjc.2016.428. ISSN 0007-0920. PMC 5318970.
  8. ↑ Neubauer A, Fiebeler A, Graham DK, O'Bryan JP, Schmidt CA, Barckow P, Serke S, Siegert W, Snodgrass HR, Huhn D (1994). "Expression of axl, a transforming receptor tyrosine kinase, in normal and malignant hematopoiesis". Blood. 84 (6): 1931–41. PMID 7521695.
  9. ↑ 9.0 9.1 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): 1058–64. doi:10.1593/neo.05640. PMC 1501169. PMID 16354588.
  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): 1124–36. doi:10.1016/j.cell.2007.10.034. PMID 18083102.
  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. U.S.A. 85 (6): 1952–6. doi:10.1073/pnas.85.6.1952. PMC 279899. PMID 3279421.
  13. ↑ 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.
  14. ↑ 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): 1316–24. doi:10.1038/onc.2013.57. PMC 3994701. PMID 23474758.
  15. ↑ Nam, James (July 20, 2017). "Gilteritinib Granted Orphan Drug Status for Acute Myeloid Leukemia". Cancer Therapy Advisor. Haymarket Media Inc.
  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

External links

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