Lapatinib in breast cancer: clinical experiences and future perspectives

Giampaglia, Marianna; Chiuri, Vincenzo Emanuele; Tinelli, Andrea; Laurentiis, Michelino De; Silvestris, Nicola; Lorusso, Vito

doi:10.1016/s0305-7372(10)70024-4

Cited by 21 publications

(23 citation statements)

References 27 publications

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“…A number of clinical studies revealed evidence for efficient tumor-cell treatment with Lapatinib [reviewed in Ref. (16)] and suggested that a combination of Trastuzumab with either Pertuzumab or Lapatinib might be a valuable option for circumventing insufficient sensitivity or resistance to Trastuzumab (17). An enhanced antiproliferative effect generated by combined tumor-cell targeting has been explained by different but complementing mechanisms of action of anti-ErbB receptor antibodies and TKIs.…”

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confidence: 99%

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

et al. 2011

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Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor-and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRGcaused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting. '

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confidence: 99%

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

et al. 2011

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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%

“…This small molecule works intra-cellularly, reversibly binding to the cytoplasmic ATP-binding site of the kinase and blocking receptor phosphorylation and activation. This interaction prevents the signal transduction of both Ras/Raf mitogen-activated protein kinases (MAPKs) and PI3K (phosphatidylinositol-3-kinase)/Akt pathways, leading to an increase in apoptosis and decrease cellular proliferation [3] (Figure 1).…”

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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“…Most frequent adverse events were including diarrhea, nausea, rash and fatigue with low rate of cardiac adverse effects. Currently numerous clinical studies are underway with various combinations (Dhillon and Wagstaff, 2007;Giampaglia et al, 2010).…”

Section: Epidermal Growth Factor Receptor (Egfr) Inhibitorsmentioning

confidence: 99%

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

Kim¹

2011

Biomolecules and Therapeutics

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In a pharmaceutical industry in which nine out of ten attempts to bring a product to market fail, oncology is among the most challenging therapeutic area (Kola and Landis, 2004;Kamb et al., 2007). In the recent article published in the Nature Rev. Drug Discov. (Arrowsmith, 2011), 83 Phase III and submission failures during 2007 to 2010 were divided according to therapeutic area and reason for failure. Largest numbers of failures was in the area of cancer (28%) followed by neurodegeneration (18%). The 66% of the failures across all therapeutic areas were attributed to lack of effi cacy and 21% of the failures were due to safety issues. Therefore, there is a desperate need for new drugs, especially in the cancer treatment.As a rational approach to cancer therapy in the middle of the last century, a new class of drug discoveries emerged to exploit the differential dependence of proliferating cancer cells on vital functions such as DNA metabolism, replication, chromosome segregation and cytokinesis. These efforts ultimately produced range of nucleoside analogues, DNA-modifying chemicals and natural products -the traditional chemotherapeutic (cytotoxic) agents. The mechanism of action of these Invited ReviewBiomol Ther 19(4), 371-389 (2011) www.biomolther.org drugs-inhibition of essential cellular functions-dictates a narrow therapeutic window (Kamb et al., 2007). A new strategy for cancer therapy has emerged during the past decade based on molecular targets that are less likely to be essential in all cells in the body, therefore more apt to confer a wider therapeutic window than traditional cytotoxic drugs (Kamb et al., 2007;Reichert and Wenger, 2008).In this review, some of the strategies and the opportunities in the molecular targeted oncology drug discovery are discussed. EXCEPTIONAL HETEROGENEITY AND ADAPTABIL-ITY OF CANCER: MAJOR CHALLENGES IN ONCOL-OGY DRUG DISCOVERYCancer is an extraordinarily heterogeneous disease with somatic alterations arise as individual cancer develops (Greenman et al., 2007;Kamb et al., 2007;Harris and McCormick, 2010). This exceptional heterogeneity of cancer is refl ected in observed differences in drug responses, and is the probable cause of acquired resistance. It is also presumably related to drug sensitivity and tumor aggressiveness which display a wide range of variation among malignancies.Due to the heterogeneity both among the cells of an individual tumor and among different cancers, the effi cacy predictions made from xenograft animal models often fail (Kamb, 2005), which presents signifi cant challenges in the oncology drug discovery where advancement of compounds largely based on a pharmacological effect in the xenograft models. Even though xenograft represents signifi cant aspects of the tumor from which it was derived, it probably captures only a fraction of the total genetic and epigenetic heterogeneity of a given tumor subtype. Low response rate in phase I oncology trials is refl ective of poor predictability of clinical effi cacy based on these xenograft mo...

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Lapatinib in breast cancer: clinical experiences and future perspectives

Cited by 21 publications

References 27 publications

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

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

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

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