BH3 mimetic drugs overcome the microenvironment-induced resistance to crizotinib in ALK+ anaplastic large cell lymphoma

: Resistance to first-line chemotherapies and crizotinib in anaplastic large cell lymphoma (ALCL) represents a significant challenge, often leading to a dismal outcome. Despite recent advancements, the dissection of the intrinsic and extrinsic molecular alterations underlying crizotinib resistance in ALCL is still poorly understood. Here, we transcriptionally unraveled the bidirectional interplay between anaplastic lymphoma kinase (ALK)-driven ALCL (ALK+ ALCL) and stromal cells in the presence of crizotinib at bulk and single-cell levels, and identified that the microenvironment provides pro-survival signals leading to crizotinib persistence in ALK+ ALCL. We detected increased BCL2 expression, and downregulation of pathways related to apoptosis in crizotinib-persister ALK+ ALCL cells. Further, we predicted in silico the ligand-receptor interactions between tumoral and stromal cells, supporting their contribution to ALCL pathogenesis mainly participating in the adhesion/membrane transport, triggering receptors, and promoting activation and microenvironment stimulation in lymphoma cells. Finally, we explored the effect of crizotinib in combination with BH3 mimetics. Pharmacologic and genetic ablation of anti-apoptotic targets displayed a significant synergistic effect with crizotinib, overcoming the stroma-mediated protection of lymphoma cells upon drug treatment. Thus, BCL2/BCL-XL targeting is synthetic lethal with crizotinib exposure in ALK+ ALCL and represents an intrinsic and extrinsic-mediated targetable vulnerability in lymphoma cells challenged with crizotinib. Our data supports the evaluation of BCL2 targeting in crizotinib-based regimens in the management of ALK+ ALCL patients.