Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitization

2008 ◽  
Vol 417 (1) ◽  
pp. 361-371 ◽  
Author(s):  
Elizabeth Iorns ◽  
Christopher J. Lord ◽  
Alan Ashworth
Keyword(s):  
Breast Cancer ◽  
Oestrogen Receptor ◽  
Kinase Inhibitors ◽  
Genetic Screen ◽  
Genetic Screens ◽  
Development Of Resistance ◽  
Chemical Screen ◽  
Related Proteins ◽  
Insight Into ◽  
Treat Breast Cancer

Tamoxifen is the most commonly used drug to treat breast cancer and acts by blocking ERα (oestrogen receptor α) signalling. Although highly effective, its usefulness is limited by the development of resistance. Given this, strategies that limit resistance by sensitizing cells to tamoxifen may be of use in the clinic. To gain insight into how this might be achieved, we used chemical and genetic screens to identify targets and small-molecule inhibitors that cause tamoxifen sensitization. A high-throughput genetic screen, using an RNA interference library targeting 779 kinases and related proteins, identified the PDK1 (phosphoinositide-dependent kinase 1) signalling pathway as a strong determinant of sensitivity to multiple ERα antagonists, including tamoxifen. A chemical screen using existing drugs and known kinase inhibitors also identified inhibitors of the PDK1 pathway, including triciribine and tetrandrine. Aside from identifying novel agents and targets for tamoxifen sensitization, this approach also provides evidence that performing chemical and genetic screens in parallel may be useful.

Recent Progress and Development of Small Molecule Kinase Inhibitors for the Treatment of Breast Cancer

2020 ◽  
Vol 16 (1) ◽  
pp. 4-19 ◽  
Author(s):  
Debasis Das ◽  
Jian Hong
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Cancer Therapy ◽  
Recent Progress ◽  
Kinase Inhibitors ◽  
Signal Transduction Pathways ◽  
Targeted Drugs ◽  
Breast Cancer Therapy ◽  
Health Burden ◽  
Treat Breast Cancer

Breast cancer, the most common health burden to women globally, is considered a major cause of death for women every year. Many signal transduction pathways can cause breast cancer. The kinase inhibitors can interrupt the signaling pathways, minimize tumor growth and consequently cure the disease. The scientists have discovered many kinase inhibitors as targeted drugs for breast cancer. In recent years, the inhibitors of EGFR, HER2, VEGFR, PI3K, CDK4/6, PARP and hormone receptor have been studied well for curing breast cancer. The FDA has approved a few kinase drugs such as trastuzumab, lapatinib, neratinib, palbociclib, abemaciclib, alpelisib to treat breast cancer recently. In this review, we summarized the latest development of kinase inhibitors as breast cancer therapy.

Recent Updates on the Therapeutic Potential of HER2 Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer

2018 ◽  
Vol 18 (4) ◽  
pp. 306-327 ◽  
Author(s):  
Heena Singla ◽  
Anjana Munshi ◽  
Raja Paramjit Singh Banipal ◽  
Vinod Kumar
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Development Of Resistance ◽  
Positive Breast Cancer

HER2 positive breast cancer is characterized by the low survival rate in the metastatic patients. Development of resistance and disease-relapse are the major problems associated with the currently available therapies for HER2 positive breast cancer. There are two major targeted therapies for HER2 positive breast cancer viz. monoclonal antibodies and tyrosine-kinase inhibitors, and both of these therapies have their advantages and limitations. To address the limitations associated with the existing therapies, use of antibodies and TKIs as combination therapy proved to be more effective. Various chemical modifications can be performed on tyrosine-kinase inhibitors to develop novel ligands with increased selectivity for HER2 kinase. A number of tyrosine-kinase inhibitors are in various phases of clinical trials for the treatment of HER2 positive breast cancer. In the current review article, recent developments on various HER2 tyrosine-kinase inhibitors have been reported. Various structurally different scaffolds bind to the HER2 receptor and exhibit potent anti-cancer activities. The structural and pharmacophoric requirements of the scaffolds are discussed in detail so as to discover effective drug candidates for the treatment of HER2 positive breast cancer.

scholarly journals New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1573 ◽  
Author(s):  
Essia Mezni ◽  
Cécile Vicier ◽  
Mathilde Guerin ◽  
Renaud Sabatier ◽  
François Bertucci ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Kinase Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Advanced Breast ◽  
Clinical Practices ◽  
Her2 Positive ◽  
Development Of Resistance ◽  
Breast Cancer Subgroup

Over the last few decades, improved knowledge of oncogenic activation mechanisms of HER2 protein has led to the development of HER2 targeted therapies that are currently commonly used in HER2-positive advanced breast cancer, such as trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine. The management of this breast cancer subgroup has thus been revolutionized and its prognosis has changed dramatically. Nevertheless, HER2-positive advanced breast cancer remains an incurable disease and resistance to conventional anti-HER2 drugs is almost unavoidable. Nowadays, biochemical and pharmaceutical advances are meeting the challenge of developing increasingly sophisticated therapies directed against HER2, including novel anti HER2 antibodies with increased affinity. New antibody-drug conjugates (ADC) with more advanced pharmacological properties, and dual targeting of epitopes via bispecific monoclonal antibodies are also emerging. In addition, more potent and more specific HER2 tyrosine kinase inhibitors have shown interesting outcomes and are under development. Finally, researchers’ interest in tumor microenvironment, particularly tumor-infiltrating lymphocytes, and the major role that signaling pathways, such as the PI3K/AKT/mTOR pathway, play in the development of resistance to anti-HER2 therapies have spurred the development of clinical trials evaluating innovative combinations of anti-HER2 with PD-1/PDL-1, CDK4/6 and PI3K inhibitors. However, several questions remain unresolved, like the optimal management of HER2-positive/HR-positive advanced breast cancer and the identification of predictive biomarkers to better define populations that can benefit most from these new therapies and approaches.

scholarly journals Targeting HER 1 and 2 in breast cancer with lapatinib

2011 ◽  
pp. 21-28
Author(s):  
Gerald M. Higa
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Family Members ◽  
Disease Relapse ◽  
Her Family ◽  
Development Of Resistance ◽  
Improved Outcomes ◽  
Insight Into

Numerous clinical trials support the biological relevance of the HER2 oncoprotein in breast cancer. In spite of improved outcomes, overexpression of the receptor is associated with increased risks of disease relapse, even in patients with early, and potentially curable, disease. Until recently, development of resistance to trastuzumab left patients with no therapeutic option other than specifically targeted HER2. This paper provides an in-depth review of lapatinib, a dual HER kinase inhibitor, as well as some insight into three HER family members, in breast cancer.

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