Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation
Identifieur interne : 000344 ( Pmc/Checkpoint ); précédent : 000343; suivant : 000345Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation
Auteurs : Markus Lauter ; Anja Weber ; Robert TorkaSource :
- Cell Communication and Signaling : CCS [ 1478-811X ] ; 2019.
Abstract
Overexpression of AXL receptor tyrosine kinase (AXL) in various human cancers correlates with reduced patients overall survival and resistance to first line therapies. Therefore, several AXL tyrosine kinase inhibitors (TKIs) are currently under clinical evaluation.
AXL TKI BMS777607 treatment increased AXL protein levels after 24 h as observed by Western blot and flow cytometry analysis. Mechanistically, this inhibition-induced AXL cell surface accumulation was neither associated with epigenetic modifications, nor altered transcriptional and translational regulation. Further, we saw no impact on glycosylation and receptor shedding by α-secretases. However, we observed that BMS777607 increased the glycosylated 140 kDa AXL protein abundance, which was impaired in the kinase dead mutant AXL (K567R). We demonstrated that AXL kinase activity and subsequent kinase phosphorylation is necessary for GAS6-dependent receptor internalization and degradation. Blocking of kinase function by BMS777607 resulted in ubiquitination prohibition, impaired internalization and subsequent cell surface accumulation. Subsequently, AXL cell surface accumulation was accompanied by increased proliferation of 3D-Speroids induced by low μM levels of BMS777607 treatment.
Our data suggest a re-evaluation of anti-AXL clinical protocols due to possible feedback loops and resistance formation to targeted AXL therapy. An alternative strategy to circumvent feedback loops for AXL targeting therapies may exist in linkage of AXL TKIs to a degradation machinery recruiting unit, as already demonstrated with PROTACs for EGFR, HER2, and c-Met. This might result in a sustained inhibition and depletion of the AXL from tumor cell surface and enhance the efficacy of targeted anti-AXL therapies in the clinic.
Url:
DOI: 10.1186/s12964-019-0377-8
PubMed: 31171001
PubMed Central: 6555758
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation</title><author><name sortKey="Lauter, Markus" sort="Lauter, Markus" uniqKey="Lauter M" first="Markus" last="Lauter">Markus Lauter</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Weber, Anja" sort="Weber, Anja" uniqKey="Weber A" first="Anja" last="Weber">Anja Weber</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Torka, Robert" sort="Torka, Robert" uniqKey="Torka R" first="Robert" last="Torka">Robert Torka</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31171001</idno><idno type="pmc">6555758</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555758</idno><idno type="RBID">PMC:6555758</idno><idno type="doi">10.1186/s12964-019-0377-8</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000054</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000054</idno><idno type="wicri:Area/Pmc/Curation">000054</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000054</idno><idno type="wicri:Area/Pmc/Checkpoint">000344</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000344</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation</title><author><name sortKey="Lauter, Markus" sort="Lauter, Markus" uniqKey="Lauter M" first="Markus" last="Lauter">Markus Lauter</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Weber, Anja" sort="Weber, Anja" uniqKey="Weber A" first="Anja" last="Weber">Anja Weber</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Torka, Robert" sort="Torka, Robert" uniqKey="Torka R" first="Robert" last="Torka">Robert Torka</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Cell Communication and Signaling : CCS</title><idno type="eISSN">1478-811X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p id="Par1">Overexpression of AXL receptor tyrosine kinase (AXL) in various human cancers correlates with reduced patients overall survival and resistance to first line therapies. Therefore, several AXL tyrosine kinase inhibitors (TKIs) are currently under clinical evaluation.</p></sec><sec><title>Results</title><p id="Par2">AXL TKI BMS777607 treatment increased AXL protein levels after 24 h as observed by Western blot and flow cytometry analysis. Mechanistically, this inhibition-induced AXL cell surface accumulation was neither associated with epigenetic modifications, nor altered transcriptional and translational regulation. Further, we saw no impact on glycosylation and receptor shedding by α-secretases. However, we observed that BMS777607 increased the glycosylated 140 kDa AXL protein abundance, which was impaired in the kinase dead mutant AXL (K567R). We demonstrated that AXL kinase activity and subsequent kinase phosphorylation is necessary for GAS6-dependent receptor internalization and degradation. Blocking of kinase function by BMS777607 resulted in ubiquitination prohibition, impaired internalization and subsequent cell surface accumulation. Subsequently, AXL cell surface accumulation was accompanied by increased proliferation of 3D-Speroids induced by low μM levels of BMS777607 treatment.</p></sec><sec><title>Conclusion</title><p id="Par3">Our data suggest a re-evaluation of anti-AXL clinical protocols due to possible feedback loops and resistance formation to targeted AXL therapy. An alternative strategy to circumvent feedback loops for AXL targeting therapies may exist in linkage of AXL TKIs to a degradation machinery recruiting unit, as already demonstrated with PROTACs for EGFR, HER2, and c-Met. This might result in a sustained inhibition and depletion of the AXL from tumor cell surface and enhance the efficacy of targeted anti-AXL therapies in the clinic.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Myers, Sh" uniqKey="Myers S">SH Myers</name></author><author><name sortKey="Brunton, Vg" uniqKey="Brunton V">VG Brunton</name></author><author><name sortKey="Unciti Broceta, A" uniqKey="Unciti Broceta A">A Unciti-Broceta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Graham, Dk" uniqKey="Graham D">DK Graham</name></author><author><name sortKey="Deryckere, D" uniqKey="Deryckere D">D DeRyckere</name></author><author><name sortKey="Davies, Kd" uniqKey="Davies K">KD Davies</name></author><author><name sortKey="Earp, Hs" uniqKey="Earp H">HS Earp</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vouri, M" uniqKey="Vouri M">M 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Commun Signal</journal-id><journal-id journal-id-type="iso-abbrev">Cell Commun. Signal</journal-id><journal-title-group><journal-title>Cell Communication and Signaling : CCS</journal-title></journal-title-group><issn pub-type="epub">1478-811X</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31171001</article-id><article-id pub-id-type="pmc">6555758</article-id><article-id pub-id-type="publisher-id">377</article-id><article-id pub-id-type="doi">10.1186/s12964-019-0377-8</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-title>Targeting of the AXL receptor tyrosine kinase by small molecule inhibitor leads to AXL cell surface accumulation by impairing the ubiquitin-dependent receptor degradation</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lauter</surname><given-names>Markus</given-names></name><address><email>Markus.Lauter@gmx.de</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Weber</surname><given-names>Anja</given-names></name><address><email>anja.weber@uk-halle.de</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4030-3535</contrib-id><name><surname>Torka</surname><given-names>Robert</given-names></name><address><phone>(+49)3455573820</phone><email>robert.torka@uk-halle.de</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0679 2801</institution-id><institution-id institution-id-type="GRID">grid.9018.0</institution-id><institution>Institute of Physiological Chemistry,</institution><institution>University Halle-Wittenberg, Medical Faculty,</institution></institution-wrap>Hollystrasse 1, 06114 Halle (Saale), Germany</aff></contrib-group><pub-date pub-type="epub"><day>6</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>6</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>17</volume><elocation-id>59</elocation-id><history><date date-type="received"><day>6</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>25</day><month>5</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s). 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p id="Par1">Overexpression of AXL receptor tyrosine kinase (AXL) in various human cancers correlates with reduced patients overall survival and resistance to first line therapies. Therefore, several AXL tyrosine kinase inhibitors (TKIs) are currently under clinical evaluation.</p></sec><sec><title>Results</title><p id="Par2">AXL TKI BMS777607 treatment increased AXL protein levels after 24 h as observed by Western blot and flow cytometry analysis. Mechanistically, this inhibition-induced AXL cell surface accumulation was neither associated with epigenetic modifications, nor altered transcriptional and translational regulation. Further, we saw no impact on glycosylation and receptor shedding by α-secretases. However, we observed that BMS777607 increased the glycosylated 140 kDa AXL protein abundance, which was impaired in the kinase dead mutant AXL (K567R). We demonstrated that AXL kinase activity and subsequent kinase phosphorylation is necessary for GAS6-dependent receptor internalization and degradation. Blocking of kinase function by BMS777607 resulted in ubiquitination prohibition, impaired internalization and subsequent cell surface accumulation. Subsequently, AXL cell surface accumulation was accompanied by increased proliferation of 3D-Speroids induced by low μM levels of BMS777607 treatment.</p></sec><sec><title>Conclusion</title><p id="Par3">Our data suggest a re-evaluation of anti-AXL clinical protocols due to possible feedback loops and resistance formation to targeted AXL therapy. An alternative strategy to circumvent feedback loops for AXL targeting therapies may exist in linkage of AXL TKIs to a degradation machinery recruiting unit, as already demonstrated with PROTACs for EGFR, HER2, and c-Met. This might result in a sustained inhibition and depletion of the AXL from tumor cell surface and enhance the efficacy of targeted anti-AXL therapies in the clinic.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>RTK</kwd><kwd>AXL</kwd><kwd>TKI</kwd><kwd>Ubiquitin</kwd><kwd>Degradation</kwd><kwd>3D spheroid</kwd></kwd-group><funding-group><award-group><funding-source><institution>HaPKom</institution></funding-source></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list></list><tree><noCountry><name sortKey="Lauter, Markus" sort="Lauter, Markus" uniqKey="Lauter M" first="Markus" last="Lauter">Markus Lauter</name><name sortKey="Torka, Robert" sort="Torka, Robert" uniqKey="Torka R" first="Robert" last="Torka">Robert Torka</name><name sortKey="Weber, Anja" sort="Weber, Anja" uniqKey="Weber A" first="Anja" last="Weber">Anja Weber</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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