Tyrosine Kinase Inhibitors in the Combination Therapy of HER2 Positive Breast Cancer

Abstract

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) accounts for about 20% to 30% of all BC subtypes and is characterized by invasive disease and poor prognosis. With the emergence of anti-HER2 target drugs, HER2-positive BC patient outcomes have changed dramatically. However, treatment failure is mostly due to drug resistance and the special treatment needs of different subgroups. Small molecule tyrosine kinase inhibitors can inhibit multiple targets of the human epidermal growth factor receptor family and activate PI3K/AKT, MAPK, PLC γ, ERK1/2, JAK/STAT, and other pathways affecting the expression of MDM2, mTOR, p27, and other transcription factors. This can help regulate the differentiation, apoptosis, migration, growth, and adhesion of normal cells and reverse drug resistance to a certain extent. These inhibitors can cross the blood-brain barrier and be administered orally. They have a good synergistic effect with effective drugs such as trastuzumab, pertuzumab, t-dm1, and cyclin-dependent kinase 4 and 6 inhibitors. These advantages have resulted in small-molecule tyrosine kinase inhibitors attracting attention. The new small-molecule tyrosine kinase inhibitor was investigated in multi-target anti-HER2 therapy, showed a good effect in preclinical and clinical trials, and to some extent, improved the prognosis of HER2-positive BC patients. Its use could lead to a de-escalation of treatment in some patients, possibly preventing unnecessary procedures along with the associated side effects and costs.

Strategies for the treatment of HER2+ advanced breast cancer based on clinical practice in Chinese patients: a roundtable discussion

“…The HER2 family involves extracellular protein overexpression and intracellular point mutations, both of which can activate the downstream pathway. Primary resistance to the dual-targeted drugs, trastuzumab + pertuzumab, can be partially reversed by TKIs such as lapatinib, pyrotinib, and neratinib ( 20 ). TKIs inhibit multiple targets of the human epidermal growth factor receptor family intracellularly and also help regulate cell growth, differentiation, migration, and apoptosis.…”

Focal Adhesion Kinase Fine Tunes Multifaced Signals toward Breast Cancer Progression

“…In this context, combination treatments based on the use of FAK inhibitors alongside chemotherapeutics, radiochemotherapeutics and immunotherapeutics would guarantee innovative options to halt the growth and metastatic spread of breast cancer. In this regard, new tyrosine kinase inhibitors (TKIs) have attracted attention in clinical settings for the synergistic repressive effects observed in combination with the endocrine therapies or monoclonal antibodies [229]. Moreover, immunotherapy combined with agents targeting VEGF, EGFR, PI3K, MEK, PARP and other chemotherapeutics has been shown to trigger clinical benefits in breast cancer patients [230,231].…”

Mechanistic Study of the Herbal Drug FDY003 for the Treatment of HER2-Positive Breast Cancer via Network Pharmacology Analysis

“…The ErbB, HIF-1, JAK-STAT, MAPK, PI3K-Akt, and Ras pathways are the primary causes of resistance to chemo-and radio-therapeutics via upregulation of the proliferative, metastatic, migratory, invasive, cancerinitiating, and EMT capacities of HER2PBC cells and tumors; therapeutic suppression of these pathways can restore treatment sensitivity [62,64,[68][69][70][71][72][73][74]. The activity of these pathways may also be a potential indicator for the treatment response rate and survival outcomes of patients with HER2PBC [62,64,[68][69][70][71][72][73][74]. The p53 pathway is a key modulator of various stress responses and repair processes in cells [67].…”