Targeting Receptor Tyrosine Kinases as a Novel Strategy for the Treatment of Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) comprises a group of aggressive and heterogeneous breast carcinoma. Chemotherapy is the mainstay for the treatment of triple-negative tumors. Nevertheless, the success of chemotherapeutic treatments is limited by their toxicity and development of acquired resistance leading to therapeutic failure and tumor relapse. Hence, there is an urgent need to explore novel targeted therapies for TNBC. Receptor tyrosine kinases (RTKs) are a family of transmembrane receptors that are key regulators of intracellular signaling pathways controlling cell proliferation, differentiation, survival, and motility. Aberrant activity and/or expression of several types of RTKs have been strongly connected to tumorigenesis. RTKs are frequently overexpressed and/or deregulated in triple-negative breast tumors and are further associated with tumor progression and reduced survival in patients. Therefore, targeting RTKs could be an appealing therapeutic strategy for the treatment of TNBC. This review summarizes the current evidence regarding the antitumor activity of RTK inhibitors in preclinical models of TNBC. The review also provides insights into the clinical trials evaluating the use of RTK inhibitors for the treatment of patients with TNBC.

Keywords: AXL; EGFR; MET; receptor tyrosine kinases; small-molecule inhibitors; triple-negative breast cancer.

Figure 1.

Prototype structure of an RTK illustrating extracellular, transmembrane, and intracellular domains. (a) The structure of the prototype receptor (EGFR) and its ligand (EGF) were obtained from the Protein Data Bank (PDB) under the accession entry of 2GS6 and 1EGF, respectively. The rendered three-dimensional structure of EGFR was obtained from Wikimedia Commons (File:126-Epidermal Growth Factor EGFR by David Goodsell under the Creative Commons Attribution 3.0 license). (b) The 20 RTK families and their corresponding structures. EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; RTK, receptor tyrosine kinase.

Figure 2.

Mechanism of RTK activation and signaling. The binding of a ligand to the extracellular domain of an RTK monomer induces receptor dimerization followed by the autophosphorylation of the intracellular kinase domain and the subsequent phosphorylation of specific tyrosine residues near the carboxy-terminus. An active RTK recruits and activates several downstream substrates and signaling pathways. RTK, receptor tyrosine kinase.

Figure 3.

The major RTKs involved in the tumorigenesis of TNBC and their downstream signaling pathways. The activation of the EGFR, MET, RON, AXL, and IGF1R activates a wide range of downstream signaling hubs for pathways associated with cancer cell proliferation, survival, migration, and invasion. The RTKs can be targeted by mAbs and small-molecule TKIs. mAbs, monoclonal antibodies; TKIs, small-molecule tyrosine kinase inhibitors; TNBC, triple-negative breast cancer.