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ROR1 sustains prosurvival signaling from multiple receptor tyrosine kinases including epidermal growth factor receptor, MET, and insulin\u2010like growth factor 1 receptor in part by maintaining the caveolae structure as a scaffold protein of cavin\u20101 and caveolin\u20101. In this study, a high throughput screening of the natural product library containing 2560 compounds was undertaken using a cell\u2010based FluoPPI assay detecting ROR1\u2010cavin\u20101 interaction. As a result, geldanamycin (GA), a known inhibitor of heat shock protein 90 (HSP90), was identified as a potential inhibitor of ROR1. Geldanamycin, as well as two GA derivatives tested in the clinic, 17\u2010allylamino\u201017\u2010demethoxygeldanamycin (17\u2010AAG) and 17\u2010dimethylaminoethylamino\u201017\u2010demethoxygeldanamycin (17\u2010DMAG), decreased ROR1 protein expression. We found that ROR1 physically interacted with HSP90\u03b1, but not with other HSP90 paralogs, HSP90\u03b2 or GRP94. Geldanamycin in turn destabilized and degraded ROR1 protein in a dose\u2010 and time\u2010dependent manner through the ubiquitin\/proteasome pathway, resulting in a significant suppression of cell proliferation in lung adenocarcinoma cell lines, for which the kinase domain of ROR1, but not its kinase activity or N\u2010glycosylation, was required. Our findings indicate that HSP90 is required to sustain expression of ROR1 crucial for lung adenosarcoma survival, suggesting that inhibition of HSP90 could be a promising therapeutic strategy in ROR1\u2010positive lung adenocarcinoma.<\/jats:p>","DOI":"10.1111\/cas.14786","type":"journal-article","created":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T23:47:55Z","timestamp":1609199275000},"page":"1225-1234","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Inhibition of heat shock protein 90 destabilizes receptor tyrosine kinase ROR1 in lung adenocarcinoma"],"prefix":"10.1111","volume":"112","author":[{"given":"Behnoush","family":"Khaledian","sequence":"first","affiliation":[{"name":"Division of Molecular Carcinogenesis Center for Neurological Diseases and Cancer Nagoya University Graduate School of Medicine Nagoya Japan"},{"name":"Division of Molecular Diagnostics Aichi Cancer Center Nagoya 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