Acquired hormone resistance is an old hurdle and still represents to be a constant challenge
in oncology for the medical community. Most recently, mainly following the results of BOLERO-2
study, the activation of the PI3K-AKT-mTOR pathway is considered clinically relevant for tumor escape
from hormone dependence in breast cancer. In the BOLERO-2 trial, a combination of everolimus,
mTOR inhibitor, and exemestane significantly prolonged the median progression free survival (PFS)
compared to exemestane alone in advanced breast cancer patients with acquired endocrine resistance. Therefore, the inhibitors
of the PI3K-AKT-mTOR pathway are a new class of drugs in great expansion joined with great expectation. This
review article focuses on this special issue and briefly reports on the results of clinical trials using PI3K-AKT-mTOR inhibitors.
However, the emergence of resistance to this new class of drugs, evidenced by the basic research and the relatively
less benefit shown in the clinical trials, has been emerging as a new undesirable complication. Therefore, the principal
elucidated mechanisms of the resistance to the inhibitors of the PI3K-AKT-mTOR pathway and the related potential
therapeutic strategies are described. A more general immunological approach to delay acquired hormone resistance has
also been considered and commented upon.