Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F23%3A00132237" target="_blank" >RIV/00216224:14110/23:00132237 - isvavai.cz</a>
Result on the web
<a href="https://www.science.org/doi/10.1126/scitranslmed.abo3826" target="_blank" >https://www.science.org/doi/10.1126/scitranslmed.abo3826</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1126/scitranslmed.abo3826" target="_blank" >10.1126/scitranslmed.abo3826</a>
Alternative languages
Result language
angličtina
Original language name
Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma
Original language description
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 ? (PI3K-?) 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. PI3K? expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3K?, and PI3Kd were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3K? 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 PI3K?/d 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 PI3K? or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.
Czech name
—
Czech description
—
Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
30204 - Oncology
Result continuities
Project
<a href="/en/project/LX22NPO5102" target="_blank" >LX22NPO5102: National institute for cancer research</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Science Translational Medicine
ISSN
1946-6234
e-ISSN
1946-6242
Volume of the periodical
15
Issue of the periodical within the volume
702
Country of publishing house
US - UNITED STATES
Number of pages
17
Pages from-to
1-17
UT code for WoS article
001021683100002
EID of the result in the Scopus database
2-s2.0-85163613436