MYC couples SWI/SNF and metabolic reprogramming to sustain minimal residual disease in mTORC1-activated cancer cells [CUT&RUN, ATAC-seq]

Therapeutics blocking PI3K-mTORC1 are commonly used for tumor treatment, and at times achieve major responses, yet minimal residual disease (MRD) persists, leading to tumor relapse. We examined the MRD models established both in vitro (Rapamycin persistent, RP) and in vivo after mTORC1 inhibition. All RP/MRD cell lines showed complete growth and signaling insensitivity to rapamycin but variable sensitivity to bi-steric mTORC1 inhibitors. MTORS2035 mutations were identified in 4 of 7 RP cell lines. Multi-omic analysis identified a pronounced shift to oxidative phosphorylation and away from glycolysis in all RP/MRD models, with increased mitochondrial number and function. MYC and SWI/SNF expression were greatly enhanced. Both the SWI/SNF inhibitor AU-15330 and the Complex I inhibitor of oxidative phosphorylation IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance.