ALK⁺ Lymphomas Harbor a Targetable Dependency on Exogenous Cholesterol

Changes in the expression of metabolic genes promote nutrient dependencies and may affect nonmetabolic processes in cancer cells that can be therapeutically exploited. To systematically identify cancer type–specific cholesterol auxotrophy, Garcia-Bermudez and colleagues performed a competitive proliferation assay with a pooled collection of 28 cancer cell lines that had been individually transduced with a lentiviral barcode library and grown in either lipoprotein-replete or lipoprotein-depleted medium. A subset of cell lines, representing a variety of cancer types, exhibited strong cholesterol dependencies but no mutations in cholesterol biosynthesis genes; analysis of the Cancer Cell Line Encyclopedia (CCLE) revealed that the cholesterol biosynthesis enzyme squalene monooxygenase (SQLE) was not expressed in the SNU-1 cell line, resulting in increased squalene accumulation in SNU-1 cells. Further examination of the CCLE identified nine additional cell lines, six of which were ALK⁺ anaplastic large cell lymphoma (ALCL) cell lines, that simultaneously lacked SQLE mRNA and protein, were sensitive to cholesterol depletion, and exhibited increased squalene accumulation. Similarly, ALK⁺ ALCL patient-derived xenografts (PDX) and primary samples exhibited decreased SQLE mRNA and protein expression compared with ALK⁻ ALCLs and other lymphomas. A CRISPR/Cas9 screen identified LDLR as critical for ALK⁺ ALCL cell line growth in vitro and ALK⁺ ALCL cell line xenograft and PDX growth in vivo. Genetic ablation of squalene synthase (FDFT1), which drives squalene synthesis, in ALK⁺ ALCL cells resulted in wild-type–like squalene levels and decreased growth in vivo. Given that squalene is lipophilic and accumulates in cellular membranes, genetic or pharmacologic inhibition of FDFT1 sensitized ALK⁺ ALCL cells to ferroptosis; treatment with an antioxidant or inhibition of polyunsaturated fatty acid incorporation into the membrane blocked ferroptosis in FDFT1-ablated ALK⁺ ALCL cells. These findings show that cholesterol dependency represents a therapeutic target in ALK⁺ ALCL, characterize the antioxidant-like properties of a metabolite, and describe a systematic approach to identify nutrient auxotrophies.

Garcia-Bermudez J, Baudrier L, Bayraktar EC, Shen Y, La K, Guarecuco R, et al. Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 2019;567:118–22..

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