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Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma
C. Mastini, M. Campisi, E. Patrucco, G. Mura, A. Ferreira, C. Costa, C. Ambrogio, G. Germena, C. Martinengo, S. Peola, I. Mota, E. Vissio, L. Molinaro, M. Arigoni, M. Olivero, R. Calogero, N. Prokoph, F. Tabbò, B. Shoji, L. Brugieres, B....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural
Odkazy
PubMed
37379367
DOI
10.1126/scitranslmed.abo3826
Knihovny.cz E-zdroje
- MeSH
- anaplastická lymfomová kináza MeSH
- anaplastický velkobuněčný lymfom * farmakoterapie genetika patologie MeSH
- endoteliální buňky metabolismus MeSH
- fosfatidylinositol-3-kinasy MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- inhibitory tyrosinkinasy MeSH
- krizotinib farmakologie terapeutické užití MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí MeSH
- nádory plic * farmakoterapie MeSH
- nemalobuněčný karcinom plic * farmakoterapie MeSH
- receptory CCR7 genetika MeSH
- tyrosinkinasové receptory metabolismus MeSH
- tyrosinkinasy MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.
Candiolo Cancer Institute FPO IRCCS Candiolo Torino 10060 Italy
Dana Farber Cancer Institute Boston MA 02115 USA
Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
Department of Mechanical and Aerospace Engineering Politecnico of Torino Torino 10129 Italy
Department of Mechanical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA
Department of Medical Science University of Torino Torino 10126 Italy
Department of Medicine and Surgery University of Milan Bicocca Monza 20900 Italy
Department of Molecular Biotechnology and Health Sciences University of Torino Torino 10126 Italy
Department of Oncology University of Torino Orbassano Torino 10043 Italy
Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA 02115 USA
Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA
Department of Pathology Cornell University New York NY 10121 USA
Department of Pre Clinical Development Catapult Therapeutics B 5 8243 RC Lelystad Netherlands
Faculty of Medicine Masaryk University Brno 601 77 Czech Republic
Harvard Medical School Boston MA 02115 USA
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