Drugging the PI3K/AKT/mTOR Pathway in ER+ Breast Cancer

Abstract

The frequent activation of the PI3K/AKT/mTOR pathway and its crucial role in estrogen receptor-positive (ER+) breast cancer tumorigenesis and drug resistance has made it a highly attractive therapeutic target in this breast cancer subtype. Consequently, the number of new inhibitors in clinical development targeting this pathway has drastically increased. Among these, the PIK3CA isoform-specific inhibitor alpelisib and the pan-AKT inhibitor capivasertib were recently approved in combination with the estrogen receptor degrader fulvestrant for the treatment of ER+ advanced breast cancer after progression on an aromatase inhibitor. Nevertheless, the clinical development of multiple inhibitors of the PI3K/AKT/mTOR pathway, in parallel with the incorporation of CDK4/6 inhibitors into the standard of care treatment in ER+ advanced breast cancer, has led to a multitude of available therapeutic agents and many possible combined strategies which complicate personalizing treatment. Here, we review the role of the PI3K/AKT/mTOR pathway in ER+ advanced breast cancer, highlighting the genomic contexts in which the various inhibitors of this pathway may have superior activity. We also discuss selected trials with agents targeting the PI3K/AKT/mTOR and related pathways as well as the rationale supporting the clinical development of triple combination therapy targeting ER, CDK4/6 and PI3K/AKT/mTOR in ER+ advanced breast cancer.

Keywords: CDK4/6 inhibitor; PI3K/AKT/mTOR pathway; estrogen receptor-positive breast cancer.

Figure 1

Schematic representation of the PI3K/AKT/mTOR pathway and its targetable regulators. RTK activation stimulates PI3K to convert PIP2 to PIP3, which recruits PDK1, AKT and mTORC2 to the plasma membrane. Both PDK1 and mTORC2 activate AKT, which activates mTORC1. A negative feedback loop is induced by mTORC1 at IRS1. The negative regulator PTEN converts PIP3 back to PIP2. GPCR, G protein-coupled receptor; RTK, receptor tyrosine kinase; IRS1, insulin receptor substrate 1; PDK1, phosphoinositide-dependent kinase 1; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate.

Figure 2

Crosstalk between the PI3K/AKT/mTOR and estrogen receptor pathways in ER+ breast cancer. The ER and PI3K/AKT/mTOR pathways interact directly and indirectly at multiple nodes of each pathway. E2, estrogen; ER, estrogen receptor; ERE, estrogen response elements; RTK, receptor tyrosine kinase.

Figure 3

The convergence of the PI3K/AKT/mTOR, cyclin D-CDK4/6-RB and estrogen receptor pathways in ER+ breast cancer. Cyclin D1 functions as a common node by regulating the cell cycle through binding to CDK4/6, inducing ligand-independent activation of ER that can conversely induce cyclin D1 expression, which is further upregulated and stabilized by downstream effectors of the PI3K/AKT/mTOR pathway. Drugs targeting various regulators of the three pathways are also depicted. E2, estrogen; ER, estrogen receptor; ERE, estrogen response elements; RTK, receptor tyrosine kinase.