The small natural product rapamycin, when bound to FKBP12, is a potent inhibitor of an evolutionarily conserved Target of Rapamycin Complex 1 (TORC1), which plays a central role in mediating cellular response to nutrient availability. Given the prominent role of TORC1 in cell growth and proliferation, clinical trials have explored the possibility of using rapamycin as an anticancer agent. Unfortunately, the percentage of patients responding favorably has been low, intensifying the need to find biomarkers able to predict rapamycin sensitivity or resistance. In this study, we elucidate the molecular mechanism underlying partial rapamycin resistance in yeast. Using the yeast deletion collection, we identified 15 deletion strains leading to partial rapamycin resistance. Among these were Cu/Zn-superoxide dismutase Sod1, copper transporter Ctr1, and copper chaperone Lys7, suggesting a role for oxidative stress in rapamycin resistance. Further analysis revealed that all 15 strains exhibit elevated levels of superoxide anions, and we show that elevated levels of reactive oxygen species specifically modify TORC1 such that it is no longer able to fully bind FKBP12:rapamycin. Therefore, elevated oxidative stress modifies TORC1 and prevents its binding to the FKBP12:rapamycin complex, ultimately leading to rapamycin resistance. These results warrant an examination into whether similar reasons explain rapamycin resistance observed in various clinical samples.
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