Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem

Abstract

Approximately 20% of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2 (HER2/ErbB2). Of these, some also express steroid receptors (the so-called Luminal B subtype), whereas others do not (the HER2 subtype). HER2 abnormal breast cancers are associated with a worse prognosis, chemotherapy resistance, and sensitivity to selected anti-HER2 targeted therapeutics. Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic; rather, the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells. Most notably, this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors, particularly the androgen receptor. We discuss members of the HER receptor tyrosine kinase family, heterodimer formation, and downstream signaling, with a focus on HER2 associated pathology in breast carcinogenesis. The development and application of anti-HER2 drugs, including selected clinical trials, are discussed. In light of the many excellent reviews in the clinical literature, our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance. These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors, targeting crosstalk between HER2 and other nuclear receptors, lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation, and metformin, a broadly inhibitory drug. We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+ invasive breast cancer patients.A robust and reliable determination of hormone receptor and HER2 "status" in newly diagnosed breast cancer is more difficult to achieve than it may seem. Some of this is due to clinical and surgical nuances of individual patient tumors, as well as the distance and time required for transportation of the biopsy, examination, and processing by pathology. Clinical teams should adhere to the most recent widely accepted practice guidelines, developed by a working group and codified by the College of American Pathologists and the American Society of Clinical Oncology (www.asco.org/breast-cancer-guidelines) [13] . These recommendations include the use of FDA approved reagents, test, and reporting methodology. Testing must be performed in a clinical laboratory improvement amendments-certified laboratory, using appropriate controls and validated assays. Each of these assays requires a pathologist to perform a semi-quantitative analysis of the cancer sample using evidence-based interpretive guidelines and visual microscopy [14] .

Mechanisms of Multidrug Resistance in Cancer Chemotherapy

“…Unfortunately, administration of the inhibitor of HER2 signaling to HER2+ breast cancer patients often results in loss of initial drug sensitivity and development of resistance to used agent. The promising novel strategy of HER2 abnormal breast cancers' clinical treatment assumes alternate combinatory agents, including cyclin-dependent kinase (CDK) 4/6 inhibitors, endocrine therapy, cholesterol pathway inhibitors, or receptor tyrosine kinase (RTK) inhibitors [49].…”

Molecular perspective on targeted therapy in breast cancer: a review of current status

“…By binding ligands to these receptors, intracellular signal pathways such as PI3K / Akt / mTOR, Ras / Raf / MEK (MAP kinase kinase) / ERK (MAP kinase) / MAPK, Src and Signal Transducer of Activators of Transcription (STAT), which regulate cell proliferation, migration, differentiation, cell motility, and apoptosis, are activated. Since HER2 does not have a known natural ligand, activation of intracellular signaling pathways occurs indirectly through dimerization with other ligand-coupled receptors [ 19 , 20 ]. TKIs such as lapatinib, neratinib, tucatinib, and pyrotinib bind to the intracelluler tyrosine kinase domains HER family members including HER2 [ 7 ].…”

“…Lapatinib ditosylate monohydrated, which is an oral 4-anilinoquinazoline derivative, reversibly binds to the cytoplasmic adenosine triphosphate (ATP) binding site of the tyrosine kinase of HER1, HER2 / ErbB2, and EGFR, subsequently prevents the receptor phosphorylation and activation, and in this way inhibit downstream signaling pathways such as ERK-1/2 ve PI3K/Akt [ 21 , 22 ]. Lapatinib dystocylate monohydrate was approved by the FDA in 2007 for the treatment of metastatic HER2 + patients who have received prior therapy such as an anthracycline, a taxane, and trastuzumab [ 23 ] and is often used with chemotherapeutics, other agents targeting HER2 such as trastuzumab or with endocrine therapy [ 20 ]. The most common side effects associated with the use of lapatinib, which is generally well tolerated like other small molecule tyrosine kinase inhibitors, are diarrhea, rash, nausea, fatigue, abdominal cramping, gastroesophageal reflux disease [ 24 ].…”

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs

“…Intrinsic mechanisms such as metabolic rewiring of tumor cells are another source of drug resistance, in particular, lipid metabolism plays an important role in this process. Thus, dysregulation of cholesterol homeostasis using drugs such as lovastatin, in combination with lapatinib, shows an enhanced therapeutic effect over lapatinib alone in HER2 BC patients (revised in [ 216 ]). Extrinsic factors such as the gut microbiota can also affect therapy response.…”