Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer

Mukherjee, Abhik; Dhadda, A.; Shehata, Mohamed; Chan, Sy

doi:10.1517/14656566.8.13.2189

Cited by 40 publications

(25 citation statements)

References 56 publications

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“…Lapatinib has recently been approved by the U.S. Food and Drug Administration for the treatment of HER2-expressing advanced breast cancer [26], and lapatinib prolonged progression-free survival in patients with HER2-overexpressing advanced or metastatic breast cancer in several clinical trials [25,[27][28][29][30]. Furthermore, we and others showed that lapatinib induces the accumulation of HER2 at the cell surface and enhances the effects of trastuzumab-mediated ADCC in breast cancer and esophageal squamous cell carcinoma [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity

et al. 2012

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Background Trastuzumab has been recently approved for clinical use to treat HER2-expressing advanced gastric cancer, and anti-HER2-targeting therapy has become a promising option for gastric cancer. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER2. The aim of the present study was to explore the utility of lapatinib for gastric cancer, with a particular focus on trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Methods Nine gastric cancer cell lines were evaluated for the effects of lapatinib on the cell-surface accumulation of HER2 and analyzed for their additional effects on trastuzumab-mediated ADCC. Also, HER2 signaling with Western blot, proliferative function with the MTT assay, and apoptosis-inducing activity with 7ADD/Annexin-V were investigated when a panel of gastric cancer cell lines was treated with lapatinib. Results Lapatinib inhibited HER2 signaling and cell proliferation in the panel of gastric cancer cell lines. Lapatinib also induced the accumulation of HER2 on the cell surface, resulting in the enhancement of trastuzumabmediated ADCC of gastric cancer. Conclusions Lapatinib exhibits inhibitory activity in gastric cancer cells, and the combination of lapatinib with trastuzumab may be a promising treatment strategy for gastric cancer patients.

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Section: Introductionmentioning

confidence: 99%

Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity

et al. 2012

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“…The simultaneous blockade of both receptors by lapatinib may be more effective than single receptor inhibition because of the propensity for HER family hetero-dimerisation and resultant signalling diversity (Mukherjee et al, 2007). Lapatinib, as monotherapy or in combination with chemotherapy, has promising anti-tumour activity in HER2 positive locally advanced or MBC as evidenced by efficacy outcome reported earlier.…”

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confidence: 99%

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

et al. 2009

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BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n ¼ 100), objective response rate was 19.0% (95% confidence interval (CI): 11.8 -28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9 -34.7). One out of 22 HER2-negative tumour was documented as complete response (n ¼ 22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P ¼ 0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

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“…Crosstalk between pathways involving the epidermal growth factor family of receptors (ErbB1 and HER2) and the estrogen receptor (ER) is involved in resistance to endocrine therapy [8][9][10]. Moreover, targeted agents have been used in preclinical models to enhance the efficacy of either tamoxifen or estrogen deprivation [1][2][3][4][5][6][7][8][9][10][11][12][13]. This constituted the rationale for using targeted agents against EGFR pathways in combination with endocrine manipulation to overcome endocrine resistance.…”

Section: Lapatinib In Combination With Endocrine Agentsmentioning

confidence: 99%

“…In preclinical studies, lapatinib demonstrated to be not cross-resistant with trastuzumab, and clinical evidence suggests that its activity does not depend on the PTEN, p95 HER2 (a truncated version of HER2 receptor) [4], IGF1R or PI3K mutation status [5,6]. Several phase II and III trials have demonstrated a substantial anti-tumor activity of lapatinib against HER2-overexpressing metastatic BC (MBC).…”

Section: Introductionmentioning

confidence: 99%

Lapatinib, a TKI Dual Inhibitor of Her1 and Her2 Receptors: Review of the Literature

Lorusso¹,

Marech²,

Giampaglia³

et al. 2012

JCT

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Lapatinib ditosylate (Tyverb ®) is a potent and selective oral dual receptor tyrosine kinase inhibitor (TKI), preventing autophosphorylation of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER2/ErbB2) intracellular domain. This interference blocks the Ras/Raf MAPKs and PI3K/Akt pathways, that lead to uncontrolled cellular proliferation and survival. After the demonstration of its effectiveness and safety in HER2-overexpressed breast cancer, in 2007 the US Food and Drug Administration (FDA) approved this molecule in combination with capecitabine, in patients with locally advanced or metastatic disease, that progressed after previous treatment with anthracyclines, taxanes and trastuzumab. In 2010, Lapatinib received approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer in combination with letrozole. The most common adverse events (AE) are: anorexia, insomnia, diarrhea and skin rash and mild cardiovascular toxicity. This paper reviews the most important studies on Lapatinib in advanced breast cancer. However, promising results were recently reported on this drug, also in adjuvant setting and in combination with other target drugs, which warrant further investigation for the future.

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Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer

Cited by 40 publications

References 56 publications

Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity

Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Lapatinib, a TKI Dual Inhibitor of Her1 and Her2 Receptors: Review of the Literature

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