PI3K/Akt

Dual PI3K/AKT/mTOR inhibitors

It has been hypothesized that blockage of the PI3K/AKT/mTOR pathway can lead to increased antitumor activity in TNBC. Preclinical data have shown that the combination of compounds targeting different cognate molecules in the PI3K/AKT/mTOR pathway leads to synergistic activity. On the basis of these findings, new compounds targeting different components of the PI3K/AKT/mTOR pathway simultaneously continue to be developed. For example, gedatolisib inhibits mutant forms of PI3K-α with elevated kinase activity at concentrations equivalent to the IC50 for wild-type PI3K-α. PI3K-β, -δ and -γ isoforms were inhibited by gedatolisib at concentrations approximately 10-fold higher than those observed for PI3K-α. Another advantage of simultaneously targeting PI3K and mTOR is the ensuing more robust inhibition of receptor tyrosine kinase-positive feedback loops seen with isolated PI3K inhibition. Gedatolisib is currently under development for the treatment of TNBC, in combination with PTK7 antibody–drug conjugate. Apitolisib (GDC-0980) is a PI3K inhibitor (subunits α, δ, and γ) that also targets mTORC