Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients.

Aberrant activation of the PI3K/Akt/mTOR pathway is found in many types of cancer and thus plays a major role in breast cancer cell proliferation and anti-cancer drug resistance. The mechanisms involved in the activation of this pathway include: constitutively activated receptor tyrosine kinases (IGF/IGFR, ErbB, FGF/FGFR systems) leading to constitutive activation of PI3K; loss of PTEN function; PI3K mutations; aberrant activation of Akt, eIF4E, 4E-BP1 and p70S6K. These alterations trigger a cascade of biological events, from cell growth and proliferation to survival and migration, which contribute to tumor progression. Therefore, the PI3K/AKT/mTOR pathway is considered an attractive target for the development of novel anti-cancer molecules, and several specific tyrosine kinase inhibitors and signal transduction inhibitors specifically targeting the kinases involved in this pathway have been developed. Many of these inhibitors currently under clinical evaluation represent a promising approach for the treatment of breast cancer patients. This review provides an overview of the most recent patents, of pre-clinical and clinical studies of inhibitors targeting the different members and/or activators of the PI3K/Akt/mTOR pathway, used alone or in combination with other targeted agents for the treatment of breast cancer.