In Edmond Rostand’s play Cyrano de Bergerac (1897), the beautiful Roxane, mistakenly believing that the love letters written by Cyrano come from the handsome Christian de Neuvillette, falls in love with the latter. It is not until the tragic end of the play that Roxane realizes she has overlooked Cyrano’s talent and passion lamenting,“I have loved but one man in my life, and I have lost him twice.” More than a century later, the age of targeted cancer therapy is on us with several agents either approved or demonstrating considerable promise. Molecular and biochemical engineering have allowed scientists to discover targets of interest, manufacture compounds that inhibit specific proteins or genes, and validate these effects in preclinical and clinical models. Three decades ago, a different paradigm existed because the target of a drug was often elucidated after its effect on tumors was established. Rapamycin, also called sirolimus, is an example of this latter process and, much like Roxane’s Cyrano, has been unnoticed for too long.

Rapamycin was initially discovered in 1975 on the island of Rapa Nui, from which it derives its name. Initially developed as an antibiotic, it was noted that rapamycin possesses antiproliferative properties, especially against lymphocytes. Thus, the agent was studied as an immunosuppressive and eventually approved for prophylaxis of renal allograft rejection. In 1991, the target of rapamycin was discovered in yeast and named target of rapamycin (TOR). 1 The only known homolog in mammals was subsequently cloned and called mammalian target of rapamycin, or mTOR. 2 Since then, we have learned a great deal about the mechanism by which rapamycin interacts with mTOR, the mTOR pathway itself, and the relevance of the pathway to diseases including cancer.