PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer

Abstract

The incidence of breast cancer brain metastases has increased in recent years, largely due to improved control of systemic disease with human epidermal growth factor receptor 2 (HER2)-targeted agents and the inability of most of these agents to efficiently cross the blood-blood barrier (BBB) and control central nervous system disease. There is, therefore, an urgent unmet need for treatments to prevent and treat HER2+ breast cancer brain metastases (BCBMs). Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently observed in many cancers, including primary breast tumors and BCBMs. Agents targeting key components of this pathway have demonstrated antitumor activity in diverse cancers, and may represent a new treatment strategy for BCBMs. In preclinical studies, several inhibitors of PI3K and mTOR have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs.

Fig. 1. The PI3K pathway in HER2+ breast cancer

4EBP1, eukaryotic initiation factor 4E-binding protein 1; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-related kinase; HER2, human epidermal growth factor receptor; INPP4B, inositol polyphosphate-4-phosphatase; IRS-1, insulin receptor substrate 1; MEK, mitogen-activated protein/ERK kinase; mTORC, mammalian target of rapamycin complex; PI3K, phosphatidylinositol 3-kinase; PIP, phosphatidylinositol 3-bisphosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; PIP₃, phosphatidylinositol 3,4,5-bisphosphate; PTEN, phosphatase and tensin homolog; S6K, ribosomal protein S6 kinase.