Simultaneous targeting of estrogen receptor and HER2 in breast cancer

Approximately 50% of HER2-positive breast cancers express estrogen receptor (ER) and these tumors are characterized by short-lived responses to hormonal agents. Preclinical models have shown that dual targeting of ER and HER2 could reverse and delay the development of drug resistance. Two studies (TAnDEM & EGF3008) have recently been published addressing the combined use of an aromatase inhibitor (AI) and an anti-HER2-targeted agent. Both studies showed that the combined approach is associated with improvement in response rate and progression-free survival compared with an AI alone with an acceptable toxicity profile. These results would indeed extend the treatment options for patients with ER/HER2-positive metastatic breast cancer. In this article, we discuss how the improved understanding of the complex cross-talk between ER and HER2 has resulted in better clinical outcomes. We analyze clinical evidence regarding the combined use of AIs and anti-HER2-targeted agents. We also touch on possible mechanisms of resistance and ways to improve research in this field.     

Therapeutic efficiency of everolimus and lapatinib in xenograft model of human colorectal carcinoma with KRAS mutation

KRAS mutation is a negative predictive prognostic factor during metastatic colorectal cancer treatment with antiepidermal growth factor receptor antibodies. For affected patients, new therapeutics must be explored. Our objective was to study efficacy of two drugs with different mechanisms of action, everolimus (mTOR inhibitor) and lapatinib (tyrosine kinase inhibitor), in a mouse xenograft model. We chose a model obtained after engraftment of a tumor originating from a human tumor collection. The patient was affected by a metastasis colorectal carcinoma resistant to cetuximab with KRAS mutation. From a previous study in mice, we know that everolimus is a P‐glycoprotein (P‐gp) substrate and that a lapatinib pretreatment increases significantly (2.6‐fold) everolimus AUC by inhibiting its intestinal P‐gp efflux. We hence tested the effect of these drugs alone or combined. Mice bearing the xenografts were divided in four groups: control, lapatinib, everolimus, and L/E group (L/E: 2 days of lapatinib 200 mg/kg and then 3 days of everolimus 1 mg/kg). Tumor volumes and treatment toxicities were evaluated. Sixteen days after treatment initiation, the group L/E was the first one in which tumor volume average was significantly lower than the one of control group (193 ± 90 vs. 395 ± 171 mm³; P = 0.0025). After 4 weeks of treatment, inhibition of tumor growth in lapatinib, everolimus, and L/E groups reached, respectively, 49, 53, and 57%. Each drug showed significant antitumor activity. Only moderate hematologic toxicity signs were observed. These results lead to new perspectives for new oral drugs in metastatic KRAS‐mutated colorectal cancer resistant to standard chemotherapy.     

Evaluation of Lapatinib Powder-Entrapped Biodegradable Polymeric Microstructures Fabricated by X-Ray Lithography for a Targeted and Sustained Drug Delivery System

An oral medication of a molecular targeted drug, lapatinib, is taken regularly to maintain the drug concentration within the desired therapeutic levels. To alleviate the need for such cumbersome administration schedules in several drugs, advanced drug delivery systems (DDSs), which can provide time-controlled and sustained drug release, have recently received significant attention. A biodegradable synthetic polymer, such as polycaprolactone (PCL), is usually used as a carrier material for DDSs. In this paper, lapatinib powder-entrapped, PCL microstructures were fabricated with a precise X-ray lithography-based method. In vitro experiments on HER2 positive-human gastric cancer derived NCI-N87 cells were performed to appraise the drug release characteristics of the fabricated DDSs. The in vitro results indicate that after the X-ray lithography process, the lapatinib powder is still working well and show time- and dose- dependent drug release efficiencies. The cell growth inhibition characteristics of one hundred 40-μm sized microstructures were similar to those of a 1 μM lapatinib solution for over 144 h. In conclusion, the developed lapatinib-entrapped PCL microstructures can be used in molecular targeted delivery and sustained release as effective cancer-targeted DDSs.     

Investigation of Antitumor Effects of Sorafenib and Lapatinib Alone and in Combination on MCF-7 Breast Cancer Cells

Background: Breast cancer evolution and tumor progression are controlled by complex interactions betweensteroid receptors and growth factor receptor signaling. Aberrant growth factor receptor signaling can augmentor suppress estrogen receptor function in hormone-dependent breast cancer cells. Thus, we aimed to investigateantitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. Materialsand Methods: Cytotoxicity of the sorafenib and lapatinib was tested in MCF-7 cells by XTT assays. 50, 25, 12.5and 6.25μM concentrations of sorafenib and 200, 100, 50 and 25μM concentrations of lapatinib were administeredalone and in combination. Results were evaluated as absorbance at 450nM and IC50 values are calculated accordingto the absorbance data Results: Both sorafenib and lapatinib showed concentration dependent cytotoxic effectson MCF-7 cells. Sorafenib exerted cytotoxic effects with an IC50 value of 32.0μM; in contrast with lapatinib theIC50 was 136.6μM. When sorafenib and lapatinib combined, lapatinib increased cytotoxic effects of sorafenib at itsineffective concentrations. Also at the concentrations where both drugs had cytotoxic effects, combination showstrong anticancer effects and killed approximately 70 percent of breast cancer cells. Conclusions: Combinationsof tyrosine kinase inhibitors and cytotoxic agents or molecular targeted therapy has been successful for manytypes of cancer. The present study shows that both sorafenib and lapatinib alone are effective in the treatmentof breast cancer. Also a combination of these two agents may be a promising therapeutic option in treatment ofbreast cancer.     

What is the Mechanism of Progression with Trastuzumab Treatment - Escape or Resistance?

Human epidermal growth factor receptor (HER) 2 overexpression, observed in 20-25 percent of invasive breast cancers, is well known to be associated with a more aggressive phenotype and poor prognosis, with resistance to certain chemotherapeutic agents. The majority of patients with metastatic breast cancer who initially respond to trastuzumab, demonstrate disease progression within 1 year of treatment initiation. Furthermore, lack of response in some patients and relapse during the course of therapy, continue to challenge researchers and clinicians. A better understanding of the fundamental mechanisms of trastuzumab action is required so that new therapies directed at HER2 can be developed. We present here findings for mechanisms, both of Trastuzumab action and clinical resistance or escape.     

EGFR和ErbB2双重酪氨酸激酶

拉帕替尼是一种人源2型表皮生长因子受体(HER2)和表皮生长因子受体(EGFR)双重酪氨酸激酶抑制剂,与卡培他滨联用治疗女性HER2阳性的乳腺癌。我们利用MEDLINE进行关键词为拉帕替尼的文献检索,对其药理作用、药动学、临床疗效及安全性,药物相互作用等进行综述。     

3D cell culture alters signal transduction and drug response in head and neck squamous cell carcinoma

Epidermal growth factor receptor (EGFR) upregulation is a typical characteristic of head and neck squamous cell carcinoma (HNSCC). However, tyrosine kinase inhibitors have not yet been able to achieve enough therapeutic benefit in clinical trials to justify their use in standard therapy regimens. At present, little is known about the reasons for this treatment failure. In the present study, the HNSCC cell lines UM-SCC-11B and UM-SCC-22B were tested for their response to tyrosine kinase inhibitors (TKI) under 2D and 3D cell culture conditions. Absorption and luciferase-based viability assays were used for this, as well as optical evaluation via fluorescence microscopy. In addition, EGFR and HER3 expression as well as the downstream signalling pathways PI3K/AKT/mTOR and RAS/RAF/MEK/ERK were investigated using western blotting. Cell line UM-SCC-11B revealed a strong resistance to lapatinib under 3D cell culture conditions, while a good response to TKI therapy was observed under 2D cell culture conditions. An associated overexpression of phosphorylated HER3 under 3D cell culture conditions offered a plausible explanation for the altered treatment response. The results of the present study represent an idea of how signalling mechanisms of cancer cells can be changed using different cell culture methods. Overall, 3D cell culture could be an important component in the analysis of resistance mechanisms in cancer therapy.