The therapeutic potential of mTOR inhibitors in breast cancer

Abstract

Rapamycin and modified rapamycins (rapalogs) have been used to prevent allograft rejection after organ transplant for over 15 years. The mechanistic target of rapamycin (mTOR) has been determined to be a key component of the mTORC1 complex which consists of the serine/threonine kinase TOR and at least five other proteins which are involved in regulating its activity. Some of the best characterized substrates of mTORC1 are proteins which are key kinases involved in the regulation of cell growth (e.g., p70S6K) and protein translation (e.g., 4E-BP1). These proteins may in some cases serve as indicators to sensitivity to rapamycin-related therapies. Dysregulation of mTORC1 activity frequently occurs due to mutations at, or amplifications of, upstream growth factor receptors (e.g., human epidermal growth factor receptor-2, HER2) as well as kinases (e.g., PI3K) and phosphatases (e.g., PTEN) critical in the regulation of cell growth. More recently, it has been shown that certain rapalogs may enhance the effectiveness of hormonal-based therapies for breast cancer patients who have become resistant to endocrine therapy. The combined treatment of certain rapalogs (e.g., everolimus) and aromatase inhibitors (e.g., exemestane) has been approved by the United States Food and Drug Administration (US FDA) and other drug regulatory agencies to treat estrogen receptor positive (ER+) breast cancer patients who have become resistant to hormonal-based therapies and have progressed. This review will summarize recent basic and clinical research in the area and evaluate potential novel therapeutic approaches.

Keywords: drug resistance; endocrine resistance; everolimus; exemestane; metastasis; rapamycin.

Figure 1

Effects of estrogen, estrogen receptor antagonists and aromatase inhibitors on ERα‐mediated signalling: (A) normal ERα‐mediated signalling; (B) estrogen receptor antagonists block ERα signalling; (C) lack of conversion of testosterone (TEST) to estrogen by aromatase inhibitors preventing conversion. SERMs = selective estrogen‐receptor modulators

Figure 2

Genetic mutations which result in activation of the Ras/PI3K/PTEN/Akt/mTORC1 and Ras/Raf/MEK/ERK signalling pathways and contribute to malignant transformation and therapy resistance. Sometimes dysregulated expression of growth factor receptors occurs by genetic mutations, translocations or genomic amplifications which can lead to activation of the Ras/Raf/MEK/ERK, Ras/PI3K/PTEN/Akt/mTORC1 and other signalling pathways. Genes in the Ras/PI3K/PTEN/Akt/mTORC1 and Ras/Raf/MEK/ERK pathways that have activating mutations detected in human cancer and proliferative diseases are indicated in red ovals and squares. Other key genes are indicated in green ovals. Red arrows indicate activating events in pathways. Blocked black arrows indicating inactivating events in pathways

Figure 3

Overview of the HER2/PI3K/PTEN/Akt/mTORC pathway and potential sites for intervention with small molecule membrane‐permeable inhibitors and monoclonal antibodies (MoAbs). The HER2 receptor is indicated in blue. In this figure it is depicted as a homodimer, although it can also heterodimerize with other EGFR family members. The downstream PI3K/PTEN/Akt/mTORC1 pathway is regulated by Ras (indicated in green ovals), PTEN indicated in a black octagon, insulin regulated substrate 1 (IRS1) Shc, Grb2, Sos and β‐catenin are indicated in orange ovals. Kinases are indicated in green ovals. The p85 regulatory subunit of PI3K (p85PI3Kα) is indicated in a green oval. The phosphatases which inhibit steps in this pathway are indicated in black octagons. TSC1 and TSC2 are indicated in black squares. PIP2 and PIP3 are indicated in yellow ovals. The mTORC1 blockers (rapalogs), PI3K and mTOR inhibitors are indicated in red octagons. The AMPK activator metformin is indicated in a green octagon. mTOR interacting proteins, which positively regulate mTOR activity, are indicated in yellow ovals. mTOR interacting proteins which negatively regulate mTOR activity are indicated in black ovals. Transcription factors activated by either ERK or Akt phosphorylation are indicated in yellow diamonds. The FKHR transcription factor that is inactivated by Akt phosphorylation is indicated by a black diamond and a white P in a black circle. FKHR is also activated by GSK‐3β phosphorylation which is indicated by a white P in a red circle. mRNA initiation factors and proteins associated with the ribosome are indicated in magenta ovals. mTORC1 phosphorylates the unc‐51‐like kinase 1 (ULK1) which results in the suppression of autophagy. ULK1 is indicated in a black oval. In contrast, AMPK activates both ULK1 and autophagy as well as TSC activity. Proteins involved in the regulation of translation are indicated in purple ovals. Red arrows indicate activating events in pathways. Black arrows indicate inactivating events in pathways. Activating phosphorylation events are depicted in red circles with Ps with a black outlined circle. Inactivating phosphorylation events are depicted in black circles with Ps with a red outlined circle