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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.<\/jats:p>","DOI":"10.1038\/s41375-025-02682-8","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T08:50:33Z","timestamp":1752137433000},"page":"2237-2245","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Targeting proteostasis in multiple myeloma through inhibition of LTK"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4158-0617","authenticated-orcid":false,"given":"Thea Kristin","family":"V\u00e5tsveen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariaserena","family":"Giliberto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valgerdur","family":"Bjornsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Centonze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrej","family":"Besse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1193-969X","authenticated-orcid":false,"given":"Yannick","family":"Frey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1630-356X","authenticated-orcid":false,"given":"Sigrid S.","family":"Sk\u00e5nland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0668-9262","authenticated-orcid":false,"given":"Anders","family":"Tveita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Alirezaylavasani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0809-3550","authenticated-orcid":false,"given":"John Franklin","family":"Imbery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8742-7028","authenticated-orcid":false,"given":"Kristine","family":"Misund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Reiterer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Zahoor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Driessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4739-7618","authenticated-orcid":false,"given":"Lenka","family":"Besse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2841-4697","authenticated-orcid":false,"given":"Kjetil","family":"Tasken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1096-0569","authenticated-orcid":false,"given":"Fredrik H.","family":"Schjesvold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hesso","family":"Farhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0344-3654","authenticated-orcid":false,"given":"Ludvig A.","family":"Munthe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"2682_CR1","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/S0021-9258(18)64385-6","volume":"236","author":"E Helmreich","year":"1961","unstructured":"Helmreich E, Kern M, Eisen HN. 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