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<p>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.</p>

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Targeting proteostasis in multiple myeloma through inhibition of LTK

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月9日

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  • Thea Kristin Våtsveen,
  • Mariaserena Giliberto,
  • Valgerdur Bjornsdottir,
  • Federica Centonze,
  • Andrej Besse,
  • Yannick Frey,
  • Sigrid S. Skånland,
  • Anders Tveita,
  • Amin Alirezaylavasani,
  • John Franklin Imbery,
  • Kristine Misund,
  • Veronika Reiterer,
  • Muhammad Zahoor,
  • Christoph Driessen,
  • Lenka Besse,
  • Kjetil Tasken,
  • Fredrik H. Schjesvold,
  • Hesso Farhan,
  • Ludvig A. Munthe

摘要

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.