MTOR Inhibition and MTOR Inhibitors in Breast Cancer

MTOR is a member of the phosphatidylinositol-3-kinase (PI3K)/AKT1/mechanistic target of rapamycin (MTOR) cell signaling pathway that affects cell growth and proliferation, protein translation and synthesis, and the regulation of apoptosis. The PI3K pathway may be activated by the binding of extracellular growth factors (e.g., IGF1, insulin-like growth factor 1) to their corresponding receptor tyrosine kinases or by activating mutations in PIK3CA, AKT1, TSC1, and others. The pathway is inhibited by phosphatase and tensin homolog (PTEN), which dephosphorylates phosphoinositide phosphates.

In patients whose tumors have demonstrated resistance to nonsteroidal aromatase inhibitors, parallel inhibition of the PI3K/AKT1/MTOR signaling pathway and the estrogen signaling pathway may provide additional improvement in efficacy.

Everolimus is a kinase inhibitor targeting MTOR approved in combination with exemestane for the treatment of postmenopausal women with HER2-negative hormone receptor positive breast cancer after failure of treatment with letrozole or anastrozole (FDA 2012). Temsirolimus in combination with letrozole has been evaluated in a randomized phase 3 trial (HORIZON) in aromatase inhibitor-naïve, hormone receptor positive breast cancer patients. The trial was stopped at the second interim analysis due to futility, and no improvement in progression-free survival was demonstrated in the temsirolimus and letrozole combination arm in comparison with letrozole plus placebo arm (Wolff et al. 2012).

MTOR Inhibitors in Breast Cancer

TORC1/2 Inhibitors in Breast Cancer

  • MLN0128

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2015. MTOR Inhibition and MTOR Inhibitors in Breast Cancer. My Cancer Genome http://www.padiracinnovation.org/content/molecular-medicine/mtor-inhibition-and-mtor-inhibitors-in-breast-cancer/ (Updated June 17).

Last Updated: June 24, 2015

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