Is Dual mTORC1 and mTORC2 Therapeutic Blockade Clinically Feasible in Cancer?
Mené sur 333 patientes atteintes d'un cancer du sein ER+ de stade métastatique (âge médian : 63 ans), cet essai de phase II compare l'efficacité, du point de vue de la survie sans progression, et la toxicité du fulvestrant en monothérapie et en combinaison avec l'évérolimus ou avec le vistusertib (un inhibiteur de mTORC1/mTORC2)
The phosphoinositide 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR) pathway is frequently altered in several human cancers. Mutational activation of this pathway has been identified to contribute to endocrine resistance in breast cancer and, hence, represents a therapeutic target in this disease. mTOR is a serine and threonine kinase downstream PI3K-AKT signaling, which nucleates 2 cellular complexes, mTORC1 and mTORC2, each with distinct subunits and selectivity for cellular substrates.1 mTORC1 is extremely sensitive to rapamycin, activates S6K, and inactivates 4EBP1, thus promoting anabolic metabolism, protein translation, and nutrient availability. The mTORC2 complex is also activated by PI3K on growth factor stimulation. It is not sensitive to rapamycin and its substrates include Ser473 AKT, SGK1, and PKC
α.
JAMA Oncology , commentaire, 2018