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.