Article

Lapatinib: A novel EGFR/HER2 tyrosine kinase inhibitor for cancer

The Royal Marsden NHS Foundation Trust, Londinium, England, United Kingdom
Drugs of today (Barcelona, Spain: 1998) (Impact Factor: 1). 08/2006; 42(7):441-53. DOI: 10.1358/dot.2006.42.7.985637
Source: PubMed

ABSTRACT Lapatinib is an oral dual tyrosine kinase inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), both frequently overexpressed in human cancer. Preclinical data have shown that lapatinib is a potent and selective inhibitor of the tyrosine kinase domain of EGFR and HER2, and tumor cells that overexpress these receptors are growth inhibited by lapatinib both in vitro and in vivo. Phase I clinical trials have shown that lapatinib is well tolerated, with mild diarrhea and rash the most frequent toxicities, and early evidence of clinical efficacy has been reported especially in HER2-positive breast cancer. Phase II studies have shown activity for lapatinib in trastuzumab-refractory breast cancer either alone or in combination with trastuzumab. When used as first-line monotherapy for advanced breast cancer, objective tumor responses have been seen in 28% of patients with untreated HER2-positive advanced breast cancer. An extensive phase III program in advanced breast cancer is now in progress both for refractory disease and as first-line therapy in combination with chemotherapy with and without trastuzumab, and with endocrine therapy. Phase II studies have also been conducted in a variety of other tumors, including renal cell cancer. Parallel biomarker studies are starting to elucidate predictive molecular phenotypes that may indicate likelihood of response to lapatinib, and these may direct future trials with this oral tyrosine kinase inhibitor.

1 Follower
 · 
99 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite the tremendous efficacy of trastuzumab against HER2-overexpressing metastatic breast cancers, a significant fraction of women demonstrate progressive disease during treatment. Multiple mechanisms have been proposed to mediate trastuzumab resistance. In this mini-review, we discuss the evidence supporting FOXM1 as a mediator of resistance and potential new therapeutic target in trastuzumab-refractory breast cancer. FOXM1 expression is significantly elevated in multiple breast cancer data sets. Some studies suggest a direct correlation between FOXM1 and HER2 expression levels. In addition, overexpression of FOXM1 reduces the sensitivity of HER2-positive breast cancer cells to trastuzumab or lapatinib. Conversely, knockdown or pharmacological inhibition of FOXM1 rescues resistance to HER2-targeted therapies. Current pre-clinical information supports further investigation of the role of FOXM1 in trastuzumab-resistant breast cancer.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Target repurposing is a proven method for finding new lead compounds that targets Trypanosoma brucei, the causative agent of human African trypanosomiasis. Due to the recent discovery of a lapatinib-derived analog 2 with excellent potency against T. brucei (EC50 = 42 nM) and selectivity over human host cells, we have explored other classes of human tyrosine kinase inhibitor scaffolds in order to expand the range of chemotypes for pursuit. Following library expansion, we found compound 11e to have an EC50 of 84 nM against T. brucei cells while maintaining selectivity over human hepatocytes. In addition, the library was tested against causative agents of Chagas’ disease, leishmaniasis, and malaria. Two analogs with sub-micromolar potencies for T. cruzi (4j) and Plasmodium falciparum (11j) were discovered, along with an analog with considerable potency against Leishmania major amastigotes (4e). Besides identifying new and potent protozoan growth inhibitors, these data highlight the value of concurrent screening of a chemical library against different protozoan parasites.
    Medicinal Chemistry Communication 11/2014; 6(2). DOI:10.1039/C4MD00441H · 2.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is the most commonly diagnosed cancer in women. The latest world cancer statistics calculated by the International Agency for Research on Cancer (IARC) revealed that 1,677,000 women were diagnosed with breast cancer in 2012 and 577,000 died. The TNM classification of malignant tumor (TNM) is the most commonly used staging system for breast cancer. Breast cancer is a group of very heterogeneous diseases. The molecular subtype of breast cancer carries important predictive and prognostic values, and thus has been incorporated in the basic initial process of breast cancer assessment/diagnosis. Molecular subtypes of breast cancers are divided into human epidermal growth factor receptor 2 positive (HER2 +), hormone receptor positive (estrogen or progesterone +), both positive, and triple negative breast cancer. By virtue of early detection via mammogram, the majority of breast cancers in developed parts of world are diagnosed in the early stage of the disease. Early stage breast cancers can be completely resected by surgery. Over time however, the disease may come back even after complete resection, which has prompted the development of an adjuvant therapy. Surgery followed by adjuvant treatment has been the gold standard for breast cancer treatment for a long time. More recently, neoadjuvant treatment has been recognized as an important strategy in biomarker and target evaluation. It is clinically indicated for patients with large tumor size, high nodal involvement, an inflammatory component, or for those wish to preserve remnant breast tissue. Here we review the most up to date conventional and developing treatments for different subtypes of early stage breast cancer.
    08/2014; 3:198. DOI:10.12688/f1000research.4340.1