Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

• Published in: Science translational medicine Vol. 15; no. 702; p. eabo3826
• Main Authors: Mastini, Cristina, Campisi, Marco, Patrucco, Enrico, Mura, Giulia, Ferreira, Antonio, Costa, Carlotta, Ambrogio, Chiara, Germena, Giulia, Martinengo, Cinzia, Peola, Silvia, Mota, Ines, Vissio, Elena, Molinaro, Luca, Arigoni, Maddalena, Olivero, Martina, Calogero, Raffaele, Prokoph, Nina, Tabbò, Fabrizio, Shoji, Brent, Brugieres, Laurence, Geoerger, Birgit, Turner, Suzanne D, Cuesta-Mateos, Carlos, D'Aliberti, Deborah, Mologni, Luca, Piazza, Rocco, Gambacorti-Passerini, Carlo, Inghirami, Giorgio G, Chiono, Valeria, Kamm, Roger D, Hirsch, Emilio, Koch, Raphael, Weinstock, David M, Aster, Jon C, Voena, Claudia, Chiarle, Roberto
• Format: Journal Article
• Language: English
• Published: United States 28.06.2023
• Subjects: Anaplastic Lymphoma Kinase; Animals; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell Line, Tumor; Crizotinib - pharmacology; Crizotinib - therapeutic use; Endothelial Cells - metabolism; Humans; Lung Neoplasms - drug therapy; Lymphoma, Large-Cell, Anaplastic - drug therapy; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - pathology; Mice; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases; Receptor Protein-Tyrosine Kinases - metabolism; Receptors, CCR7 - genetics; Tumor Microenvironment; Tyrosine Kinase Inhibitors
• DOI: 10.1126/scitranslmed.abo3826

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.