2. Academic Validation
  3. Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

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

  • Sci Transl Med. 2023 Jun 28;15(702):eabo3826. doi: 10.1126/scitranslmed.abo3826.
Cristina Mastini 1,  Marco Campisi 2 3 4,  Enrico Patrucco 1,  Giulia Mura 1,  Antonio Ferreira 5,  Carlotta Costa 1,  Chiara Ambrogio 1,  Giulia Germena 1,  Cinzia Martinengo 1,  Silvia Peola 1,  Ines Mota 3,  Elena Vissio 6,  Luca Molinaro 7,  Maddalena Arigoni 1,  Martina Olivero 6 8,  Raffaele Calogero 1,  Nina Prokoph 9,  Fabrizio Tabbò 10,  Brent Shoji 5,  Laurence Brugieres 11,  Birgit Geoerger 11 12,  Suzanne D Turner 9 13,  Carlos Cuesta-Mateos 14,  Deborah D'Aliberti 15,  Luca Mologni 15,  Rocco Piazza 15,  Carlo Gambacorti-Passerini 15,  Giorgio G Inghirami 10,  Valeria Chiono 4,  Roger D Kamm 16 17,  Emilio Hirsch 1,  Raphael Koch 2 18 19,  David M Weinstock 2 18,  Jon C Aster 5,  Claudia Voena 1,  Roberto Chiarle 1 3
Affiliations

Affiliations

  • 1 Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
  • 2 Dana Farber Cancer Institute, Boston, MA 02115, USA.
  • 3 Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Mechanical and Aerospace Engineering, Politecnico of Torino, Torino 10129, Italy.
  • 5 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston MA 02115, USA.
  • 6 Department of Oncology, University of Torino, Orbassano, Torino 10043, Italy.
  • 7 Department of Medical Science, University of Torino, Torino 10126, Italy.
  • 8 Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino 10060, Italy.
  • 9 Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  • 10 Department of Pathology, Cornell University, New York NY 10121, USA.
  • 11 Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif 94805, France.
  • 12 Université Paris-Saclay, INSERM U1015, Villejuif 94805, France.
  • 13 Faculty of Medicine, Masaryk University, Brno 601 77, Czech Republic.
  • 14 Department of Pre-Clinical Development, Catapult Therapeutics B.V., 8243 RC, Lelystad, Netherlands.
  • 15 Department of Medicine and Surgery, University of Milan-Bicocca, Monza 20900, Italy.
  • 16 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 17 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 18 Harvard Medical School, Boston, MA 02115, USA.
  • 19 University Medical Center Göttingen, 37075 Göttingen, Germany.
PMID: 37379367 DOI: 10.1126/scitranslmed.abo3826
Abstract

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.

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