Targeting proteostasis in multiple myeloma through inhibition of LTK

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Authors	VATSVEEN Thea Kristin GILIBERTO Mariaserena BJORNSDOTTIR Valgerdur CENTONZE Federica BEŠŠE Andrej FREY Yannick SKANLAND Sigrid S TVEITA Anders ALIREZAYLAVASANI Amin IMBERY John Franklin MISUND Kristine REITERER Veronika ZAHOOR Muhammad DRIESSEN Christoph BEŠŠE Lenka TASKEN Kjetil SCHJESVOLD Fredrik H FARHAN Hesso MUNTHE Ludvig A
Year of publication	2025
Type	Article in Periodical
Magazine / Source	Leukemia
MU Faculty or unit	Faculty of Medicine
Citation
web	https://www.nature.com/articles/s41375-025-02682-8
Doi	https://doi.org/10.1038/s41375-025-02682-8
Attached files	Targeting_proteostasis_in_multiple_myeloma_through_inhibition_of_LTK.pdf
Description	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.
Related projects:	National institute for cancer research