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Significance The clinical effectiveness of FDA-approved anticancer rapalogs is limited because resistance is observed in multiple-tumor settings. In order to improve the efficacy of rapalogs, there is a need to improve our ability to predict and overcome rapamycin resistance. Here we report that high FRAT1/2 expression confers rapamycin resistance by excluding GSK3 from the nucleus in multiple-cancer cell lines. FRAT1 expression is frequently high in multiple cancers, and our observations provide evidence for using FRAT1/2 expression as a biomarker for rapamycin sensitivity. Moreover, our findings reveal a major mechanism for how mTORC1 regulates nuclear protein phosphorylation and signaling, and uncover a potential therapeutic approach for targeting mTORC1-driven cancers.

Regulation of GSK3 cellular location by FRAT modulates mTORC1-dependent cell growth and sensitivity to rapamycin