Personalized drug combinations to overcome trastuzumab resistance in HER2-positive breast cancer

Abstract

HER2-positive (HER2+) breast cancer accounts for 18%-20% of all breast cancer cases and has the second poorest prognosis among breast cancer subtypes. Trastuzumab, the first Food and Drug Administration-approved targeted therapy for breast cancer, established the era of personalized treatment for HER2+ metastatic disease. It is well tolerated and improves overall survival and time-to-disease progression; with chemotherapy, it is part of the standard of care for patients with HER2+ metastatic disease. However, many patients do not benefit from it because of resistance. Substantial research has been performed to understand the mechanism of trastuzumab resistance and develop combination strategies to overcome the resistance. In this review, we provide insight into the current pipeline of drugs used in combination with trastuzumab and the degree to which these combinations have been evaluated, especially in patients who have experienced disease progression on trastuzumab. We conclude with a discussion of the current challenges and future therapeutic approaches to trastuzumab-based combination therapy.

Keywords: Combination approaches; HER2-positive breast cancer; Targeted therapy; Trastuzumab resistance.

Figure 1

Inhibitors of epidermal growth factor receptors (HER) combined with trastuzumab in active clinical practice. There are 4 members of the HER family, HER1–4. Each is composed of 3 domains: an extracellular domain that is responsible for ligand binding, a transmembrane domain, and the intracellular tyrosine kinase domain, which interacts with intracellular signaling molecules. Currently, there are 4 approaches to inhibiting HER: i) Monoclonal antibodies, including trastuzumab, pertuzumab, and MM111, to inhibit its dimerization; ii) small molecule inhibitors (lapatinib, neratinib, and afatinib) to inhibit its kinase activation; iii) toxin-conjugated antibodies to selectively target toxic agents to HER2-overexpressing BC cells; and iv) HSP90 inhibitors to rapidly degrade HER2, 3, and 4. However, this strategy (iv) has not resulted in encouraging clinical benefits in HER2+ BC patients.

Figure 2

Schematic representation of drugs used with trastuzumab to target HER2-mediated signaling. This includes dual blocking of PI3K and mTOR activity (NVP-BEZ235), mTORC1 inhibitors (everolimus and ridaforolimus), PI3K inhibitors (GDC-0941 and NVP-BKM120), Akt inhibitor (MK2206), and histone deacetylase inhibitors (dacinostat and panobinostat).

Figure 3

Therapeutic strategies targeting VEGF and IGF signaling that are undergoing active clinical development for patients whose disease is resistant to trastuzumab. For VEGF signaling, these include using bevacizumab to block secreted VEGF to bind to its receptors, and the small molecule, pazopanib, which inhibits the kinase activation of VEGFR-1, -2, and -3. The monoclonal antibody cixutumumab, which specifically targets the extracellular domain of IGF-1R, and the small molecular tyrosine kinase inhibitor BMS-754807 are promising treatments for trastuzumab-resistant patients.