Targeted therapies in breast cancer: New challenges to fight against resistance

Abstract

Breast cancer is the most common type of cancer found in women and today represents a significant challenge to public health. With the latest breakthroughs in molecular biology and immunotherapy, very specific targeted therapies have been tailored to the specific pathophysiology of different types of breast cancers. These recent developments have contributed to a more efficient and specific treatment protocol in breast cancer patients. However, the main challenge to be further investigated still remains the emergence of therapeutic resistance mechanisms, which develop soon after the onset of therapy and need urgent attention and further elucidation. What are the recent emerging molecular resistance mechanisms in breast cancer targeted therapy and what are the best strategies to apply in order to circumvent this important obstacle? The main scope of this review is to provide a thorough update of recent developments in the field and discuss future prospects for preventing resistance mechanisms in the quest to increase overall survival of patients suffering from the disease.

Keywords: Angiogenesis; Breast cancers; Human epidermal growth factor receptor 2; Immune tolerance; Resistance; Triple negative.

Figure 1

A schematic diagram of the most common resistance mechanisms to targeted therapies. (1) Alteration of the drug target (Treat.): This type of resistance involves mutations as well as amplifications of drug targets such as kinases; (2) Upstream and downstream pathway effect through the activation of receptor tyrosine kinase (RTK) (a) and/or the mutation/amplification of upstream (b) or downstream (c) components; (3) Bypass mechanisms occur as a result of a second receptor tyrosine kinase activation (a), through a mutation of a parallel kinase (b) or modulation of mRNA binding proteins (c). These alternative mechanisms of resistance especially through kinases activation result in the modification of gene expression via the phosphorylation or transcription factors (TF).

Figure 2

Resistance mechanisms to anti-angiogenic therapy. During the initial development, tumor cells that are in the core of the tumor, become hypoxic and secrete pro-angiogenic factors (a); Proangiogenic factors are also produced by immune cells (b) and bone marrow cell participate in tumor vascularization (c); The amplification of cancer cell genome stimulates high gene expression levels, consequently, requiring an increased anti-angiogenic drug concentration (d); Tumors have evolved to switch from various modes of vascularization, in order to ensure a sufficient supply of nutrients, such as sprouting angiogenesis, vasculogenesis, vessel co-option as well as vascular mimicry (e); Various pro-angiogenic factors that are redundant of VEGF are secreted by tumor and stromal cells in malignant cancers (f); In response to the treatments, blood vessels regress (g) and tumor cell produced alternative proangiogenic prolymphangiogenic factors with the development of a lymphatic network (h); Tumor cells also express immune checkpoints proteins resulting in immune tolerance (i).