Therapeutics: Mammalian target of rapamycin (mTOR; FRAP; RAFT1); mTOR complex 1 (mTORC1); mTORC2

In vitro and mouse studies suggest a bivalent compound that inhibits two mTOR domains could help treat breast cancers harboring drug-resistant mutations in one or both domains. The bivalent compound consisted of the generic mTOR antagonist rapamycin, which targets the protein's FRB domain, conjugated via a linker to TAK-228, which binds the protein's kinase domain. In human breast cancer cell lines harboring drug-resistant mutations in the FRB domain, kinase domain or both domains, the compound decreased viability compared with rapamycin plus TAK-228 or either agent alone. In a mouse xenograft model of rapamycin-resistant breast cancer, the compound decreased tumor growth with comparable potency to TAK-228. In a mouse xenograft model of TAK-228-resistant breast cancer, the compound decreased tumor growth with comparable potency to rapamycin. Next steps by Kura Oncology Inc. could include testing the bivalent compound in mouse models of breast cancer harboring drug-resistant mutations in both mTOR domains.

Rapamycin is marketed to treat transplant rejection. ...