Våtsveen Thea Kristin, Giliberto Mariaserena, Bjornsdottir Valgerdur, Centonze Federica, Besse Andrej, Frey Yannick, Skånland Sigrid S, Tveita Anders, Alirezaylavasani Amin, Imbery John Franklin, Misund Kristine, Reiterer Veronika, Zahoor Muhammad, Driessen Christoph, Besse Lenka, Tasken Kjetil, Schjesvold Fredrik H, Farhan Hesso, Munthe Ludvig A
Precision immunotherapy alliance (PRIMA), Institute of Clinical Medicine, Department of Immunology, University of Oslo, Oslo, Norway.
KG Jebsen Centre for B cell malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Leukemia. 2025 Jul 9. doi: 10.1038/s41375-025-02682-8.
Multiple myeloma (MM) cells secrete high levels of immunoglobulin and are therefore addicted to mechanisms that maintain proteome homeostasis (proteostasis). While proteasome inhibitors that target the degradative aspect of proteostasis have proven effective, only limited attempts have been made to target protein secretion. Here we show that the receptor tyrosine kinase LTK is a regulatory node in the proteostasis network that responds to secretory load and helps cells maintain a high secretory output. LTK is a highly similar paralog to ALK and by repurposing existing ALK inhibitors, we demonstrate that targeting LTK causes immunoglobulin retention, ER stress and subsequent apoptosis of primary MM cells, even in patients refractory to proteasome inhibitors. Thus, LTK is a novel therapeutic target in the biosynthetic pathway of proteostasis, with significant potential for MM treatment.
多发性骨髓瘤（MM）细胞分泌高水平的免疫球蛋白，因此依赖于维持蛋白质组稳态（蛋白质稳态）的机制。虽然靶向蛋白质稳态降解方面的蛋白酶体抑制剂已被证明有效，但针对蛋白质分泌的尝试却很有限。在这里，我们表明受体酪氨酸激酶LTK是蛋白质稳态网络中的一个调节节点，它对分泌负荷做出反应，并帮助细胞维持高分泌量。LTK是与ALK高度相似的旁系同源物，通过重新利用现有的ALK抑制剂，我们证明靶向LTK会导致免疫球蛋白滞留、内质网应激以及原发性MM细胞随后的凋亡，即使在对蛋白酶体抑制剂难治的患者中也是如此。因此，LTK是蛋白质稳态生物合成途径中的一个新的治疗靶点，在MM治疗中具有巨大潜力。
