Targeting mTORC1 Activity to Improve Efficacy of Radioligand Therapy in Cancer

SIMPLE SUMMARY: Targeted radionuclide therapy (TRT) delivers cancer-selective radiopharmaceuticals to eradicate cancer cells while sparing healthy tissue. The recent development of combinatory treatments is a growing research field in nuclear medicine to enhance cancer cytotoxicity of TRT. Among promising combinatorial strategies, this review focuses on the rationale, efficacy, and safety of targeting the mammalian target of rapamycin complex 1 (mTORC1) to improve systemic radiation with radiolabeled ligands in cancer patients. ABSTRACT: Radioligand therapy (RLT) represents an effective strategy to treat malignancy by cancer-selective delivery of radioactivity following systemic application. Despite recent therapeutic successes, cancer radioresistance and insufficient delivery of the radioactive ligands, as well as cytotoxicity to healthy organs, significantly impairs clinical efficacy. To improve disease management while minimizing toxicity, in recent years, the combination of RLT with molecular targeted therapies against cancer signaling networks showed encouraging outcomes. Characterization of the key deregulated oncogenic signaling pathways revealed their convergence to activate the mammalian target of rapamycin (mTOR), in which signaling plays an essential role in the regulation of cancer growth and survival. Therapeutic interference with hyperactivated mTOR pathways was extensively studied and led to the development of mTOR inhibitors for clinical applications. In this review, we outline the regulation and oncogenic role of mTOR signaling, as well as recapitulate and discuss mTOR complex 1 (mTORC1) inhibition to improve the efficacy of RLT in cancer.