scholarly journals Lapatinib, a Dual-Targeted Small Molecule Inhibitor of EGFR and HER2, in HER2-Amplified Breast Cancer: From Bench to Bedside

2011 ◽  
Vol 3 ◽  
pp. CMT.S3783 ◽  
Author(s):  
Roger Y. Tsang ◽  
Saeed Sadeghi ◽  
Richard S. Finn
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Clinical Data ◽  
Transmembrane Domain ◽  
Kinase Inhibitor ◽  
Extracellular Domain ◽  
Type I ◽  
Her2 Positive ◽  
Her 2

The HER-2/neu gene product is a 185 kDa Type I receptor tyrosine kinase which consists of an extracellular domain, transmembrane domain, kinase domain, and cytoplasmic tail. The initial discovery that amplification and subsequent overexpression of the HER-2/neu oncogene plays a pivotal role in the pathogenesis of 20%–25% of breast cancers has since led to significant clinical advances in the management of this subtype of breast cancer. The first approved HER2-targeted therapy, trastuzumab, is a humanized monoclonal antibody against the extracellular domain of HER2 and has demonstrated survival benefits in both the metastatic and adjuvant settings. Lapatinib, a small molecule tyrosine kinase inhibitor of both the epidermal growth factor receptor (EGFR) and HER2 is now also approved for advanced HER2-amplified breast cancer and is currently being evaluated in the adjuvant setting. Importantly, lapatinib has been shown to have activity in women with HER2-amplified breast cancer that is refractory to trastuzumab. In addition, it has been shown to extend survival in the front-line setting in combination with letrozole for estrogen receptor (ER) positive, HER2-positive breast cancer. Here we will review the biologic rationale and pre-clinical data that drove its initial clinical development as well as current clinical data and ongoing studies.

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

2020 ◽  
Vol 19 ◽  
pp. 153303382096214
Author(s):  
Xue Yang ◽  
Dapeng Wu ◽  
Shengli Yuan
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

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.

Effect of neratinib (N) alone and in combination with trastuzumab (T) in HER2-positive breast cancer (BC) cell lines.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 632-632
Author(s):  
Alexandra Canonici ◽  
Kasper Pedersen ◽  
Naomi Walsh ◽  
John Crown ◽  
Norma O'Donovan
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Combined Treatment ◽  
Clinical Problem ◽  
Resistant Cell ◽  
Her2 Positive ◽  
Her 2 ◽  
Resistant Cells

632 Background: HER-2, a member of the transmembrane receptor tyrosine kinase ErbB family, is over-expressed in approximately 25% of BC. HER-2 targeted therapies, in particular, T, a monoclonal antibody targeting HER-2, and lapatinib (L), a reversible HER-2 tyrosine kinase inhibitor, have been shown to significantly improve the prognosis for HER-2 positive BC patients. However, resistance to T and/or L is a significant clinical problem. The aim of this study is to assess the activity of N (HKI-272), an irreversible HER-2 tyrosine kinase inhibitor, in HER-2 overexpressing BC cell lines, including T and/or L resistant cells. Methods: Using proliferation assays, the effect of N was assessed alone and in combination with T in HER-2 positive BC cell lines, including T and/or L resistant cell lines. The effect of N on HER-2 and downstream signalling molecules, Erk and Akt, was determined by immunoblotting. Results: HER-2 positive BC cell lines, including T and/or L resistant cells, are sensitive to N alone with IC50 values (concentration which inhibits 50% of growth) ranging from 1 to 280 nM. The combination of N and T has additive effects in SkBR3 and BT474 which are sensitive to T and also in SKBR3-Lwhich are resistant to L. In the cell lines HCC1954, HCC1954-L, MDA-MB-453, JIMT1 and SKBR3-HL which are resistant to T, combined treatment with T and N showed no enhancement compared to N alone. Finally, N decreased phosphorylation of HER-2, Erk and Akt in all cell lines tested. Conclusions: Our results suggest that N should be studied in patients with HER-2 positive BC, including patients with T and/or L resistant BC. We also demonstrate that N in combination with T may be more effective than either agent alone in T sensitive cells.

scholarly journals Patient with metastatic breast cancer, HER2-positive, trastuzumab- and pertuzumab-resistant responding to lapatinib

ABOUTOPEN ◽  
2018 ◽  
Vol 4 (1) ◽  
pp. 66-68
Author(s):  
Daniela Cianniello ◽  
Roberta Caputo
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Breast Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Hepatic Metastases ◽  
Metastatic Breast ◽  
Her2 Positive ◽  
Metastatic Breast Carcinoma

Lapatinib is an intracellular tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2) receptors, approved for the treatment of metastatic breast carcinoma pre-treated with anti-HER2 antibodies. We report the case of a 60-year-old woman diagnosed with metastatic breast neoplasm, HER2-positive, progressing after treatment with trastuzumab, pertuzumab and T-DM1, who obtained a regression of hepatic metastases after treatment with lapatinib-capecitabine (Oncology).

scholarly journals Trichostatin A Suppresses EGFR Expression through Induction of MicroRNA-7 in an HDAC-Independent Manner in Lapatinib-Treated Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Chih-Yen Tu ◽  
Chia-Hung Chen ◽  
Te-Chun Hsia ◽  
Min-Hsiang Hsu ◽  
Ya-Ling Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor ◽  
Trichostatin A ◽  
Her2 Positive ◽  
Independent Manner ◽  
Dual Inhibitor ◽  
Egfr Expression

Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, has been shown to improve the survival rate of patients with advanced HER2-positive breast cancers. However, the off-target activity of lapatinib in inducing EGFR expression without tyrosine kinase activity was demonstrated to render HER2-negative breast cancer cells more metastatic, suggesting a limitation to the therapeutic effectiveness of this dual inhibitor in HER2-heterogeneous tumors. Therefore, targeting EGFR expression may be a feasible approach to improve the anticancer efficiency of lapatinib-based therapy. Inhibition of HDAC has been previously reported to epigenetically suppress EGFR protein expression. In this study, however, our data indicated that treatment with HDAC inhibitors trichostatin A (TSA), but not suberoylanilide hydroxamic acid (SAHA) or HDAC siRNA, can attenuate both protein and mRNA expressions of EGFR in lapatinib-treated triple-negative breast cancer cells, suggesting that TSA may suppress EGFR expression independently of HDAC inhibition. Nevertheless, TSA reduced EGFR 3′UTR activity and induced the gene expression of microRNA-7, a known EGFR-targeting microRNA. Furthermore, treatment with microRNA-7 inhibitor attenuated TSA-mediated EGFR suppression. These results suggest that TSA induced microRNA-7 expression to downregulate EGFR expression in an HDAC-independent manner.

Does lapatinib, a small-molecule tyrosine kinase inhibitor, constitute a breakthrough in the treatment of breast cancer?

Breast Cancer ◽  
2007 ◽  
Vol 14 (2) ◽  
pp. 156-162 ◽  
Author(s):  
Yoshinori Ito ◽  
Nahomi Tokudome ◽  
Tsutomu Sugihara ◽  
Shunji Takahashi ◽  
Kiyohiko Hatake
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Small Molecule ◽  
Kinase Inhibitor
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