To test the hypothesis that bi-steric mTORC1-selective inhibition may be effective in overcoming multiple forms of therapy-resistance in ER+ breast cancers, we determined the potential of RMC-6272 in the context of resistance to standard of care therapies in ER+ breast cancer including therapeutics targeting estrogen signaling and CDK4/6 kinases. Here, CDK4 is linked to breast carcinoma.