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