Treatment strategies targeting the phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin pathway against triple-negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is an exceptionally aggressive subtype of breast cancer with a poor prognosis. TNBC patients have limited treatment options beyond conventional chemotherapy, and they face significant challenges associated with disease recurrence and resistance to chemotherapy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway plays a pivotal role in cell proliferation, growth, metabolism, and survival. Its aberrant activation is closely linked to the development and progression of TNBC, as well as treatment response and drug resistance. Currently, numerous targeted drugs specifically inhibiting this signaling pathway are being developed and undergoing clinical trials. These include inhibitors targeting PI3K, AKT, or mTOR individually, as well as dual-target or multi-target inhibitors simultaneously targeting different components of this pathway. Encouragingly, some inhibitors have demonstrated promising potential in clinical trials. This review delves into the therapeutic potential of the PI3K/AKT/mTOR signaling pathway for TNBC and explores prospects for drug discovery.

Keywords: Biomarkers; Inhibitors; Mechanistic target of rapamycin; Natural products; Phosphoinositide 3-kinase; Protein kinase B; Therapy; Triple negative breast cancer.

Figure 1

Representation of phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin sequential signaling pathway in breast cancer. RTKs: Receptor tyrosine kinases; PI3K: Phosphoinositide 3-kinase; PIP: Piperine; PTEN: Phosphatase and tensin homolog; ERK: Extracellular signal-regulated kinase; AKT: Protein kinase B; mTOR: Mechanistic target of rapamycin; PDK1: 3-phosphoinositide dependent protein kinase-1; GSK-3: Glycogen synthase kinase 3; PRAS40: 40-kDa proline-rich protein kinase B substrate; FOXO1: Forkhead box O1; BAD: Bcl-2 agonist of cell death; MDM2: Murine double minute 2.

Figure 2

The key points discussed in this study. TNBC: Triple negative breast cancer; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; mTOR: Mechanistic target of rapamycin; TYMS: Thymidylate synthase; GBP2: Guanylate-binding protein 2; ACTL8: Actin-like protein 8; OPN: Osteopontin; ROR2: Receptor tyrosine kinase-like orphan receptor 2; Nrf3: Nuclear factor erythroid-2-like factor 3; QC: Quercetin; PAB: Pseudolaric acid B; Tan IIA: Tanshinone IIA; BJE: Brucea javanica seed; RTEs: Radix tetrastigma extracts; PIP: Piperine; BBM: Berbamine; HHT: Homoharringtonine.