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In this study, using human MM cell lines (KMS\u201011, OCI\u2010My5, and ANBL\u20106), we generated <jats:italic>FAM46C<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> cell clones and examined the effect of disruption of <jats:italic>FAM46C<\/jats:italic> on cell survival and cellular signaling. Cell proliferation assays showed increased clonogenicity of <jats:italic>FAM46C<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> KMS\u201011 cells compared to WT cells. Xenograft experiments showed significantly shorter overall survival of mice harboring the <jats:italic>FAM46C<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> cell\u2010derived tumors than mice with the <jats:italic>FAM46C<jats:sup>WT<\/jats:sup><\/jats:italic> cell\u2010derived tumors. Notably, levels of phosphorylated Akt and its substrates increased both in vitro and in vivo in the <jats:italic>FAM46C<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> cells compared to WT cells. In addition, caspase activities decreased in the <jats:italic>FAM46C<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> cells. Results of gene set enrichment analysis showed that loss of <jats:italic>FAM46C<\/jats:italic> significantly activated serum\u2010responsive genes while inactivating phosphatase and tensin homolog (PTEN)\u2010related genes. Mechanistically, loss of FAM46C decreased the PTEN activity, number of apoptotic cells, and caspase activities. PF\u201004691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased <jats:italic>FAM46C<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> MM cell survival. Collectively, this study is the first to report that loss of <jats:italic>FAM46C<\/jats:italic> triggers the concomitant activation of the PI3K\u2010Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in the <jats:italic>FAM46C<\/jats:italic> gene.<\/jats:p>","DOI":"10.1111\/cas.14386","type":"journal-article","created":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T20:14:49Z","timestamp":1584389689000},"page":"1663-1675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Biallelic loss of <i>FAM46C<\/i> triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells"],"prefix":"10.1111","volume":"111","author":[{"given":"Jo","family":"Kanasugi","sequence":"first","affiliation":[{"name":"Division of Hematology Department of Internal Medicine Aichi Medical University Nagakute 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