MTOR and cancer: Therefore, many issues are still to be addressed in the near future, as follows: (1) we are currently not aware of how cancer cells develop resistance to CDK4/6 and mTOR inhibitors; therefore, the best treatment after progression on these drugs is still unknown; (2) the best sequencing of all available treatment options still needs to be identified; and (3) how combinations of CDK4/6 inhibitors plus endocrine therapy and mTOR inhibitors plus endocrine therapy work compared with each other and with chemotherapy remains unknown.