CCR7-PI3K signaling supports resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

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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. While resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer (NSCLC), 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 PI3K signaling through the CCR7 chemokine receptor. We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3K expression was predictive of lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3K, and PI3K were upregulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3K isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a 3D microfluidic chip, endothelial cells, that produce the CCR7 ligands CCL19/CCL21, protected ALCL cells from apoptosis induced by crizotinib. The PI3K/ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts (PDXs). Further, genetic deletion of CCR7 blocked the central nervous system (CNS) 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 as well as the survival of persister lymphoma cells in ALCL.

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Science Translational Medicine
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American Association for the Advancement of Science
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European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675712)
The work has been supported by grants R01 CA196703-01 to RC; Leukemia & Lymphoma Society (LLS) SCOR grant to D.W., R.C., G.I., J.C.A; European Union Horizon 2020 Marie Sklodowska-Curie Innovative Training Network (ITN-ETN) Grant, Award No.: 675712 for the European Research Initiative for ALK-Related Malignancies (ERIA) to N.P., S.D.T., I.M., C.G-P., R.C.; The FANTOM Marie Sklodowska-Curie Innovative Training Network (ITN-ETN) within the Horizon Europe – the Framework Programme for Research and Innovation (2021-2027) to S.D.T., C.G-P., C.V., R.C; the MAPPYACTS trial by the Institut National du Cancer grant PHRC-K14–175 to B.G.; the Foundation ARC grant MAPY201501241 to B.G.; the Association Imagine for Margo to B.G.; MFAG 9479 to C.A.; M.C. was supported by the MIT-POLITO grant (BIOMODE – Compagnia di San Paolo) under the joint “Doctorate of Bioengineering and Medical-Surgical Sciences” of University of Turin and Politecnico di Torino, and Fondazione “Franco e Marilisa Caligara; C.A. laboratory is supported by the Giovanni Armenise–Harvard Foundation; the research leading to these results has received funding from AIRC under IG 2019 – ID. 23146 – P.I. Voena Claudia and IG-24828 – P.I. Luca Mologni.