Promising molecular targeted therapies in breast cancer

Abstract

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.

Keywords: Breast cancer; chemotherapy; targeted therapy.

Figure 1

Overview intracellular signal transduction pathways involved in the proliferation and progression of breast cancer. Targeted therapy agents discussed in this review and their main inhibition targets are illustrated. EGF: Epidermal growth factor; EGFR: EGF receptor; HGF: hepatocyte growth factor; c-MET: mesenchymal– epithelial transition factor; PDGF: Platelet-derived growth factor; PDGFR: PDGF receptor; IGF-1: insulin-like growth factor-I; IGF-1R: IGF-1 receptor; PI3K: phosphatidylinositol 3-kinase; Ras: Rat sarcoma subfamily of GTPases; AKT: protein kinases B; PDK1: pyruvate dehydrogenase kinase isozyme 1; mTOR: mammalian target of rapamycin; MEK: mitogen-activated protein kinase kinase; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; BRAF: B-type RAF kinase; src: v-Src (Rous sarcoma virus) tyrosine kinase; BCRABL: Philadelphia chromosome; JAK/STAT: Janus kinases/signal transducers and activators of transcription; PTEN: phosphatase and tensin homolog; HDAC: histone deacetylases.