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Alliance"],"accepted":{"date-parts":[[2026,4,17]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:p>\n                    The NEDD8-activating enzyme (NAE), comprising NAE1 and UBA3, is an anticancer target. The relative contribution of each of these subunits toward NAE inhibitor (NAEi) efficacy remains unclear. We demonstrated a profound interdependence of NAE1 and UBA3 expression. UBA3 reduction augmented NAEi sensitivity, whereas its overexpression led to decreased sensitivity.\n                    <jats:italic>UBA3<\/jats:italic>\n                    deficiency enhanced RKO xenograft sensitivity to SOMCL-19-133 (NAEi), which was reversed by UBA3 restoration. Cells with naturally low UBA3 expression were highly NAEi-sensitive. The criticality of UBA3 in NAEi sensitivity is not completely unexpected given that the ability of NAEi to directly bind to UBA3 is known. TCGA data showed that rectum adenocarcinoma patients with low\n                    <jats:italic>UBA3<\/jats:italic>\n                    mRNA had poorer prognoses, and 27.16% of tumors expressed low\n                    <jats:italic>UBA3<\/jats:italic>\n                    mRNA. We propose that low\n                    <jats:italic>UBA3<\/jats:italic>\n                    expression may serve as a NAEi sensitivity biomarker, particularly given that MLN4924 (NAEi) phase 3 failures may be due to a lack of patient stratification. Therefore, our key findings, on the criticality of UBA3 in NAEi sensitivity, underpin future clinical evaluations.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202503589","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T06:21:46Z","timestamp":1776493306000},"page":"e202503589","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["UBA3 reduction sensitizes cancer cells to NAE inhibitors"],"prefix":"10.26508","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5014-5312","authenticated-orcid":true,"given":"Yu-Ling","family":"Miao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/022syn853","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica","place":[", Shanghai, 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