Tumor-specific pathways of therapy resistance in ALK-rearranged lymphoma
Harvard Medical School [Boston, USA]
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 largely elucidated in ALK-driven non-small cell lung cancer (NSCLC), they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Not only do a subset of ALK+ lymphomas exhibit primary resistance to ALK TKIs, but also those tumors that go into remission for years quickly relapse upon TKI suspension, likely due to a rapid expansion of drug-resistant persister cells. To elucidate mechanisms of resistance, we used RNAseq on patient samples to identify genes that were differentially expressed in ALK TKI-resistant tumors versus ALK TKI-responsive tumors and found that resistance was associated with increased PI3K signaling. In TKI resistant ALCL lines, we observed a selective increase of PI3Kγ expression, while PI3Kδ was profoundly suppressed by the ALK oncogenic activity via STAT3 signaling. PI3Kγ over-expression was sufficient to induce TKI resistance in ALCL cells and was predictive of lack of response in patients. In mice, a constitutively active PI3Kγ isoform accelerated ALK-mediated lymphomagenesis and reduced survival. Targeting PI3Kγ with the PI3Kγ/δ dual inhibitor duvelisib showed limited efficacy as monotherapy but potentiated the ALK TKI crizotinib in vitro and in vivo in cell lines and patient-derived xenografts (PDXs). Mechanistically, PI3Kγ was required for the full activation of the MAPK pathway induced by the CCR7 chemokine-receptor that is expressed on ALK+ primary lymphoma cell and ALCL lines. In 3D microchip models, endothelial cells, that produce CCL19/21 to engage CCR7, protected ALCL CCR7WT more than CCR7KO cells from apoptosis induced by crizotinib. In mice, treatment with crizotinib completely blocked the perivascular growth of CCR7KO but not CCR7WT ALCL. Overall, the activation of PI3Kγ via the CCR7 receptor acts as a bypass pathway to sustain MAPK activation during TKI inhibition. We envision that concomitant blockade of PI3Kγ and/or the CCR7 receptor during ALK TKI treatment would reduce primary resistance as well as the survival of persister lymphoma cells in the perivascular niche.