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 Pediatric and Adolescent Oncology Gustave Roussy Cancer Center Paris Saclay University Villejuif 94805 France

Department of Pre Clinical Development Catapult Therapeutics B 5 8243 RC Lelystad Netherlands

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge CB2 0QQ UK

Faculty of Medicine Masaryk University Brno 601 77 Czech Republic

Harvard Medical School Boston MA 02115 USA

Université Paris Saclay INSERM U1015 Villejuif 94805 France

University Medical Center Göttingen 37075 Göttingen Germany

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Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma