Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

Kondo, Norio; Tsukuda, Mamoru; Ishiguro, Yoshio; Kimura, Machiko; Fujita, Kyoko; Sakakibara, Atsuko; Takahashi, Hideaki; Tóth, Gábor; Matsuda, Hideki

doi:10.3892/or_00000720

Cited by 43 publications

(25 citation statements)

References 34 publications

(45 reference statements)

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“…The anti-tumor effects following HER2 blockade in ARK2 and EnCa1 xenografts were associated with increased apoptosis and decreased proliferation as has been shown in lung and head and neck carcinomas (41, 42), as well as reduced levels of signaling proteins of the PI3K and MAPK pathways. The most potent acute abrogation of p-Erk, p-Akt, p-PRAS40 and p-p70S6K was seen following dual treatment with lapatinib and trastuzumab, supporting a rationale for the synergistic inhibition of tumor growth observed.…”

Section: Discussionmentioning

confidence: 63%

Dual HER2 Targeting Impedes Growth of HER2 Gene–Amplified Uterine Serous Carcinoma Xenografts

Groeneweg

Hernández

Byron

et al. 2014

Clinical Cancer Research

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Purpose Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient derived xenografts (PDXs). Experimental Design Immunohistochemistry and fluorescence in situ hybridization were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2 and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib or the combination of trastuzumab and lapatinib. Acute and chronic post treatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation. Results HER2 gene amplification (24%) correlated significantly with HER2 protein over-expression (55%). All models were impervious to single agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2 amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant anti-tumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2 amplified models, and was associated with increased apoptosis and decreased proliferation. Conclusions While trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2 amplified USC and may be a promising avenue for future investigation.

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Section: Discussionmentioning

confidence: 63%

Dual HER2 Targeting Impedes Growth of HER2 Gene–Amplified Uterine Serous Carcinoma Xenografts

Groeneweg

Hernández

Byron

et al. 2014

Clinical Cancer Research

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“…However, there were significant differences in the response of individual tumors to lapatinib treatment, evident by the wide range of IC50 concentrations (38). Another study evaluating the combined effect of lapatinib with either cisplatin or paclitaxel found additive effects both in vivo and in vitro (40). Lapatinib reduced proliferation of HNSCC cells, but no correlation was found between expression levels of EGFR or HER2 and the anti-proliferative effects (40).…”

Section: Her2 Inhibitorsmentioning

confidence: 99%

“…To date, 20 manuscripts have been reported in the peer-reviewed literature assessing HER2 expression in HNSCC tumors (14-33). Six papers have evaluated HER2 targeting in HNSCC preclinical models, and 2 trials have been completed and reported using HER2 inhibitors for this malignancy (18, 34-40). In this review, we will evaluate the preclinical and clinical data implicating HER2 as a therapeutic target in HNSCC.…”

Section: Introductionmentioning

confidence: 99%

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Pollock

Grandis

2015

Clinical Cancer Research

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The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. Current standard of care is surgery followed by adjuvant radiation therapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC.

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“…In several clinical trials, lapatinib demonstrated activity in HER2 overexpressing breast cancer patients and prolonged progression-free survival in patients with advanced, Herceptin-refractory disease (24). It also was shown that lapatinib in combination with chemotherapy agents, such as cisplatin or paclitaxel, have a synergistic antitumor effect in cancers with EGFR and HER2 amplification (25). Recently, it was reported that lapatinib can inhibit cell growth in EGFR and HER2 overexpressing esophageal cancer cell lines and the combination therapy of lapatinib with cetuximab or trastuzumab is a promising strategy in the treatment of esophageal cancer (26).…”

Section: Introductionmentioning

confidence: 99%

Lapatinib, a dual inhibitor of EGFR and HER2, has synergistic effects with 5-fluorouracil on esophageal carcinoma

et al. 2012

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Abstract. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) amplification occurs in over 30% of esophageal carcinomas. Combination therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for esophageal cancer. We evaluated the antitumor effects of lapatinib, a dual tyrosine kinase inhibitor which simultaneously inhibits EGFR and HER2, 5-fluorouracil (5-Fu) alone and in combination on esophageal cancer cells. The antiproliferative activity of lapatinib, 5-Fu and lapatinib plus 5-Fu was measured by MTT assay and the combination index (CI) values were calculated. Additionally, cell cycle distribution of lapatinib alone and the combination with 5-Fu were detected by flow cytometry analysis. Annexin V-FITC and propidium iodide stain were used for analyzing the apoptotic cells after cells were treated with either agent alone or in combination. The EGFR and HER2 activated signaling pathways were monitored by western blotting. The combination of lapatinib and 5-Fu synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect on esophageal cancer cells. The potentiation effect of combined treatment was associated with downregulation of EGFR and HER2 signaling pathways because data from western blot analysis showed that lapatinib in combination with 5-Fu markedly reduced the phosphorylation of EGFR and HER2, and inhibited the activation of downstream signaling molecules, such as AKT and ERK. A significant G1 arrest was also observed in cell cycle analysis after exposing cells to lapatinib, however, combination with 5-Fu did not enhance G1 arrest. These results indicate that the combination of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma with HER2 amplification.

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Antitumor effects of lapatinib (GW572016), a dual inhibitor of EGFR and HER-2, in combination with cisplatin or paclitaxel on head and neck squamous cell carcinoma

Cited by 43 publications

References 34 publications

Dual HER2 Targeting Impedes Growth of HER2 Gene–Amplified Uterine Serous Carcinoma Xenografts

Dual HER2 Targeting Impedes Growth of HER2 Gene–Amplified Uterine Serous Carcinoma Xenografts

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Lapatinib, a dual inhibitor of EGFR and HER2, has synergistic effects with 5-fluorouracil on esophageal carcinoma

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