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Mammalian Target of Rapamycin Inhibitors in Breast Cancer Therapy

Obiageli Ezewuiro, MD1, Cynthia X Ma, MD, PhD2, and Gini F Fleming, MD1

The mammalian target of rapamycin (mTOR) is a central target of the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway that transmits extra- and intracellular signals critical to growth, metabolism, motility, survival, and angiogenesis. Aberrant activation of the PI3K/mTOR pathway is a common phenomenon observed in all subtypes of breast cancer, including luminal A, luminal B, basal-like, and HER2-enriched subtypes, although the occurrence and frequency of the mechanisms responsible for such activation differ as a result of the complex and heterogeneous genetic make-up of breast cancer [1]. In a recent report by the Cancer Genome Atlas Network, PIK3CA, which encodes the alpha catalytic subunit of PI3K, was one of only three genes mutated in >10% of all breast cancers, with the highest frequency observed in the luminal/estrogen receptor (ER)-positive and HER2-enriched subtypes [1]. On the other hand, loss of tumor suppressor phosphatase and tensin homologue (PTEN) or inositol polyphosphate 4-phosphatase-II (INPP4B), the two negative regulators of the PI3K pathway, was most common in basal-like/triple-negative breast cancer (TNBC). There is increasing evidence that activation of the PI3K/mTOR pathway is a major resistance mechanism to various treatments, including endocrine therapy, HER2-targeted agents, and chemotherapy, and inhibitors against the PI3K/mTOR pathway are being actively investigated as therapeutic strategies for breast cancer. The rapamycin analogue everolimus has recently gained US Food and Drug Administration (FDA) approval for use in combination with exemestane for the treatment of non-steroidal aromatase inhibitor-resistant metastatic ER-positive breast cancer. In this review, we provide an introduction to the functions of the PI3K/mTOR pathway, mechanisms of mTOR activation, and preclinical rationale for mTOR inhibition, and highlight the major published clinical trials of rapamycin analogue mTOR inhibitors as therapeutics for breast cancer.

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