mTOR Biology and the Growing Role for mTOR Inhibitors in the Management of Breast Cancer

Elisavet Paplomata, MD, and Ruth O’Regan, MD
Published: Friday, Mar 27, 2015
Dr. Elisavet Paplomata

Elisavet Paplomata, MD

Abstract

The PI3K/Akt/mTOR pathway stimulates protein synthesis, angiogenesis, and tumor proliferation and is an important target in multiple malignancies. Its activation has been implicated in resistance to endocrine agents, chemotherapy, and HER2-directed agents. The combination of PI3K/Akt/mTOR pathway inhibition with traditional or targeted agents may overcome this resistance.

Everolimus is approved for the treatment of advanced hormone receptor-positive breast cancer and is currently being evaluated in other breast cancer subtypes. Ongoing studies are also assessing biomarkers that will help define the patients who will derive the most benefit.

Introduction

The PI3K (phosphoinositide-3-kinase)/Akt (protein kinase B)/mTOR (mechanistic target of rapamycin) pathway responds to nutrient availability and growth factor tyrosine kinases. It plays a significant role in stimulating protein synthesis, angiogenesis and tumor proliferation, and inhibiting apoptosis.1

The pathway starts with the PI3K unit, which comprises two subunits, the regulatory (p85) and the catalytic (p110) subunit; each has different isoforms and is encoded by its corresponding genes. The regulatory subunit is encoded by PIK3R1, PIK3R2, PIK3R3 and the p110α, p110β, and p110δ subunits are encoded by PIK3CA, PIK3CB and PIK3CD.2 PI3K leads to the phosphorylation of Akt, a serine/threonine kinase, which activates the mechanistic (or mammalian) target of rapamycin (mTOR) by inhibiting the tuberous sclerosis complex proteins 1/2 (TSC1/2).3-5 mTOR is a serine/threonine protein kinase that consists of complexes mTORC1 (mTOR Complex 1) and mTORC2 (mTOR Complex 2). mTORC1 is the main target of rapamycin analogs, while more recent data suggest that mTORC2 is also inhibited with sufficient dosing and exposure (Figure 1).6,7

Everolimus is approved by the FDA (Food and Drug Administration) for the treatment of hormone receptor (HR)-positive breast cancer in postmenopausal women who had previously experienced disease progression or recurrence with a non-steroidal aromatase inhibitor, based on the BOLERO-2 trial.8

This review will focus on the current data of mTOR inhibitors in breast cancer. However, as the role of mTOR inhibition in breast cancer is evolving, ongoing studies are evaluating biomarkers that will identify the patients who will benefit.

The Role of mTOR Pathway in Breast Cancer

Aberrations of the PI3K/Akt/mTOR pathway have been implicated in the pathogenesis and growth of multiple malignancies. PIK3CA is the most common mutation found in breast cancer and is thought be oncogenic.9-11

The mTOR pathway has been implicated in trastuzumab resistance in HER2-overexpressing breast cancer.12,13 HER2-targeted therapy resistance has been associated with loss of PTEN, PI3K phosphorylation, and activation of mTOR.14,15 mTOR inhibition can sensitize HER2-overexpressing breast cancer to HER2-directed therapy.16 In HR-positive breast cancer, the PI3K/Akt/mTOR signaling pathway can stimulate ERα (Estrogen Receptor Alpha) in both an estrogen-dependent and estrogen-independent manner17,18; thus, activation of the mTOR pathway appears to be involved in endocrine resistance.19-21 Preclinical data has demonstrated that inhibition of mTOR can restore hormone sensitivity, promote cell cycle arrest, and induce apoptosis when used in combination with endocrine therapy.22-25 In triple negative breast cancer models, mTOR was also found to be activated and to mediate invasiveness and metastasis.26,27

In conclusion, preclinical data demonstrate that activation of the mTOR pathway plays a role in the pathogenesis, promotion of invasiveness, and the development of resistance in various subtypes of breast cancer; this supports the further evaluation of mTOR inhibition in breast cancer, specifically in cancers that are resistant to standard therapies.

Clinical Data

Multiple clinical studies have evaluated the role of mTOR inhibition in breast cancer. Several landmark trials have shown its benefit especially in the HR-positive setting. Phase 3 clinical data have led to the approval of everolimus with exemestane in postmenopausal women with HR-positive, HER2-negative metastatic breast cancer.

HR-positive Breast Cancer


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TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
Community Practice Connections: Oncology Best Practice™ Targeting Cell Cycle Progression: The Latest Advances on CDK4/6 Inhibition in Metastatic Breast CancerOct 31, 20181.0
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