The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines

HER2 overexpression is observed in 5-25% of gastric cancers. Lapatinib is a dual inhibitor of the epidermal growth factor receptor and HER2 tyrosine kinase. We examined the antitumor effect of lapatinib in gastric cancer cell lines. Lapatinib induced selective and potent growth inhibition in two HER2-amplified gastric cancer cell lines (SNU-216 and NCI-N87). Lapatinib inhibited the phosphorylation of HER2, EGFR and downstream signaling proteins, resulting in G1 arrest in both cell lines with down-regulation of cMyc and induction of p27kip1. Lapatinib also induced apoptosis in NCI-N87 which has high HER2 amplification ratio. Lapatinib combined with 5-fluorouracil, cisplatin, oxaliplatin or paclitaxel showed an additive or synergistic effect. These results provide a rationale for the future clinical trials of lapatinib combined with cytotoxic drugs in the treatment of HER2-positive gastric cancer.     

Heregulin induces resistance to lapatinib‐mediated growth inhibition of HER2‐amplified cancer cells

Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 20% of gastric and gastroesophageal junction cancers in the United States and European Union. Lapatinib, a dual HER2 and epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated clinical efficacy in HER2‐amplified cancer cells. However, several studies have shown that some cytokines can mediate resistance to lapatinib using their receptor tyrosine kinase (RTK) pathways. One of these, Heregulin1 (HRG1), can confer resistance to lapatinib‐mediated growth inhibition in HER2‐amplified breast cancer cells, but the underlying mechanisms remain unknown. Here, we investigated whether and how HRG1 causes resistance to lapatinib in gastric and gastroesophageal junction cancers in vitro. HER2‐amplified gastric and gastroesophageal junction cancer cell lines were highly sensitive to lapatinib. Exposure to HRG1 together with lapatinib rescued cells from lapatinib‐induced cell cycle arrest and apoptosis. Downregulation of HER3 with siRNA in the presence of HRG1 re‐sensitized HER2‐amplified cancer cells to lapatinib. Immunoblotting analysis indicated that HRG1 re‐activated HER3 and AKT in the presence of lapatinib, which persisted for at least 72 h. Activation of HER3 and downstream AKT was mediated by residual activity of HER2. HRG1‐mediated resistance could be reduced by PI3K/mTOR inhibitors or by complete inhibition of HER2. Thus, we conclude that HRG1 mediates resistance to lapatinib through HER3 and AKT activation, and that this depends on residual HER2 activity. Lapatinib in combination with anti‐PI3K therapies or more potent HER2 inhibitors would improve the efficacy and avoid the emergence of resistant cells.     

The dual EGFR/HER‐2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN‐38

Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER‐2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN‐38, the active metabolite of irinotecan (CPT‐11), in colon and gastric cancer cell lines. Concentration‐dependent antiproliferative effects of both lapatinib and SN‐38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08–11.7 μM; SN‐38 range 3.6–256 nM). Lapatinib potently inhibited the growth of a HER‐2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER‐2 expression. The combination of lapatinib and SN‐38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN‐38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN‐38 when compared to SN‐38 treatment alone. Finally, the combination of lapatinib and CPT‐11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT‐11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas. © 2009 UICC     

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

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 trastuzumab-mediated 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.     

Inhibition of the Growth of Patient-Derived Pancreatic Cancer Xenografts with the MEK Inhibitor Trametinib Is Augmented by Combined Treatment with the Epidermal Growth Factor Receptor/HER2 Inhibitor Lapatinib

Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.     

Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib.     

Quercetin‐3‐methyl ether inhibits lapatinib‐sensitive and ‐resistant breast cancer cell growth by inducing G2/M arrest and apoptosis

Lapatinib, an oral, small‐molecule, reversible inhibitor of both EGFR and HER2, is highly active in HER2 positive breast cancer as a single agent and in combination with other therapeutics. However, resistance against lapatinib is an unresolved problem in clinical oncology. Recently, interest in the use of natural compounds to prevent or treat cancers has gained increasing interest because of presumed low toxicity. Quercetin‐3‐methyl ether, a naturally occurring compound present in various plants, has potent anticancer activity. Here, we found that quercetin‐3‐methyl ether caused a significant growth inhibition of lapatinib‐sensitive and ‐resistant breast cancer cells. Western blot data showed that quercetin‐3‐methyl ether had no effect on Akt or ERKs signaling in resistant cells. However, quercetin‐3‐methyl ether caused a pronounced G₂/M block mainly through the Chk1‐Cdc25c‐cyclin B1/Cdk1 pathway in lapatinib‐sensitive and ‐resistant cells. In contrast, lapatinib produced an accumulation of cells in the G₁ phase mediated through cyclin D1, but only in lapatinib‐sensitive cells. Moreover, quercetin‐3‐methyl ether induced significant apoptosis, accompanied with increased levels of cleaved caspase 3, caspase 7, and poly(ADP‐ribose) polymerase (PARP) in both cell lines. Overall, these results suggested that quercetin‐3‐methyl ether might be a novel and promising therapeutic agent in lapatinib‐sensitive or ‐resistant breast cancer patients. © 2011 Wiley Periodicals, Inc.     

In Pancreatic Carcinoma, Dual EGFR/HER2 Targeting with Cetuximab/Trastuzumab Is More Effective than Treatment with Trastuzumab/Erlotinib or Lapatinib Alone: Implication of Receptors' Down-regulation and Dimers' Disruption

We previously demonstrated the synergistic therapeutic effect of the cetuximab (anti-epidermal growth factor receptor [EGFR] monoclonal antibody, mAb)-trastuzumab (anti-HER2 mAb) combination (2mAbs therapy) in HER2^low human pancreatic carcinoma xenografts. Here, we compared the 2mAbs therapy, the erlotinib (EGFR tyrosine kinase inhibitor [TKI])-trastuzumab combination and lapatinib alone (dual HER2/EGFR TKI) and explored their possible mechanisms of action. The effects on tumor growth and animal survival of the three therapies were assessed in nude mice xenografted with the human pancreatic carcinoma cell lines Capan-1 and BxPC-3. After therapy, EGFR and HER2 expression and AKT phosphorylation in tumor cells were analyzed by Western blot analysis. EGFR/HER2 heterodimerization was quantified in BxPC-3 cells by time-resolved FRET. In K-ras-mutated Capan-1 xenografts, the 2mAbs therapy gave significantly higher inhibition of tumor growth than the erlotinib/trastuzumab combination, whereas in BxPC-3 (wild-type K-ras) xenografts, the erlotinib/trastuzumab combination showed similar growth inhibition but fewer tumor-free mice. Lapatinib showed no antitumor effect in both types of xenografts. The efficacy of the 2mAbs therapy was partly Fc-independent because F(ab′)₂ fragments of the two mAbs significantly inhibited BxPC-3 growth, although with a time-limited therapeutic effect. The 2mAbs therapy was associated with a reduction of EGFR and HER2 expression and AKT phosphorylation. BxPC-3 cells preincubated with the two mAbs showed 50% less EGFR/HER2 heterodimers than controls. In pancreatic carcinoma xenografts, the 2mAbs therapy is more effective than treatments involving dual EGFR/HER2 TKIs. The mechanism of action may involve decreased AKT phosphorylation and/or disruption of EGFR/HER2 heterodimerization.     

Lapatinib: a novel dual tyrosine kinase inhibitor

Lapatinib is an active and well-tolerated oral dual tyrosine kinase inhibitor that is able to inhibit epidermal growth factor receptor (EGFR) and HER2 with high specificity. It has shown promising activity in several cancers most notably metastatic breast cancer. Lapatinib is active in both trastuzumab-refractory and -naïve breast cancer and a number of phase III studies are ongoing to fully define its activity. Studies have also been conducted in a range of other cancers including renal cell carcinoma. It is essential that future studies incorporate predictive biomarker subgroup analysis. This will help to ensure that important subgroup activity is not missed and also allow the definition of groups most likely to benefit from lapatinib.     

Lapatinib, a preventive/therapeutic agent against mammary cancer, suppresses RTK-mediated signaling through multiple signaling pathways

Activation of receptor tyrosine kinases (RTK) plays a key role in the prognosis of mammary cancer. Lapatinib is a small molecule dual RTK inhibitor that targets epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Identifying the protein targets involved in the effects of lapatinib and other RTK inhibitors might help determine why preventive efficacy varies. In this study, female Sprague-Dawley rats were given methylnitrosourea (MNU) by intravenous injection resulting in the development of multiple estrogen receptor-positive tumors. Treatment with lapatinib beginning 5 days after MNU was highly effective in preventing cancer development. In addition, we treated rats with palpable mammary tumors with lapatinib daily. In these tumor-bearing animals, treatment continued for 42 days and therapeutic results were obtained. Some rats bearing cancers were treated for 5 days, and the resulting lesions were examined for biomarker modulation. Lapatinib effectively suppressed the abundance of HER2, phosphorylated HER2 (Tyr1221/1222), and phosphorylated EGFR (Tyr1173, Tyr1110) compared with tumors from untreated rats. Protein array analyses allowed parallel determination of the effect of lapatinib on the relative levels of protein phosphorylation and proteins associated with apoptosis. These results combined with immunoreactivity data indicated that, in addition to EGFR and HER2, lapatinib treatment was associated with changes in a number of other signaling molecules, including IGF-1R, Akt, and downstream targets such as GSK3, p27, p53, and cyclin D1 presumably leading to impaired proliferation, apoptosis, or cell-cycle arrest.     

Gemcitabine‐induced epithelial‐mesenchymal transition‐like changes sustain chemoresistance of pancreatic cancer cells of mesenchymal‐like phenotype

Growing body of evidence suggests that epithelial‐mesenchymal transition (EMT) is a critical process in tumor progression and chemoresistance in pancreatic cancer (PC). The aim of this study was to analyze the role of EMT‐like changes in acquisition of resistance to gemcitabine in pancreatic cells of the mesenchymal or epithelial phenotype. Therefore, chemoresistant BxPC‐3, Capan‐2, Panc‐1, and MiaPaca‐2 cells were selected by chronic exposure to increasing concentrations of gemcitabine. We show that gemcitabine‐resistant Panc‐1 and MiaPaca‐2 cells of mesenchymal‐like phenotype undergo further EMT‐like molecular changes mediated by ERK‐ZEB‐1 pathway, and that inhibition of ERK1/2 phosphorylation or ZEB‐1 expression resulted in a decrease in chemoresistance. Conversely, gemcitabine‐resistant BxPC‐3 and Capan‐2 cells of epithelial‐like phenotype did not show such typical EMT‐like molecular changes although the expression of the tight junction marker occludin could be found decreased. In pancreatic cancer patients, high ZEB‐1 expression was associated with tumor invasion and tumor budding. In addition, tumor budding was essentially observed in patients treated with neoadjuvant chemotherapy. These findings support the notion that gemcitabine treatment induces EMT‐like changes that sustain invasion and chemoresistance in PC cells.     

Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms

In the era of new and mostly effective molecular targeted therapies, human epidermal growth factor receptor 2 positive (HER2+) cancers are still intractable diseases. Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor, has greatly improved breast cancer prognosis in recent years after the initial introduction of trastuzumab (Herceptin). However, clinical evidence indicates the existence of both primary unresponsiveness and secondary lapatinib resistance, which leads to the failure of this agent in HER2+ cancer patients. It remains a major clinical challenge to target the oncogenic pathways with drugs having low resistance. Multiple pathways are involved in the occurrence of lapatinib resistance, including the pathways of receptor tyrosine kinase, non-receptor tyrosine kinase, autophagy, apoptosis, microRNA, cancer stem cell, tumor metabolism, cell cycle, and heat shock protein. Moreover, understanding the relationship among these mechanisms may contribute to future tumor combination therapies. Therefore, it is of urgent necessity to elucidate the precise mechanisms of lapatinib resistance and improve the therapeutic use of this agent in clinic. The present review, in the hope of providing further scientific support for molecular targeted therapies in HER2+ cancers, discusses about the latest findings and new concepts on molecular mechanisms underlying lapatinib resistance.     

Combined effects of lapatinib and bortezomib in human epidermal receptor 2 (HER2)‐overexpressing breast cancer cells and activity of bortezomib against lapatinib‐resistant breast cancer cells

Lapatinib and bortezomib are highly active against breast cancer cells. Breast cancer patients who initially respond to lapatinib may eventually manifest acquired resistance to this treatment. Thus, the identification of novel agents that may prevent or delay the development of acquired resistance to lapatinib is critical. In the current study, we show that the combination of lapatinib and bortezomib results in a synergistic growth inhibition in human epidermal receptor 2 (HER2)‐overexpressing breast cancer cells and that the combination enhances apoptosis of SK‐BR‐3 cells. Importantly, we found that the combination of lapatinib plus bortezomib more effectively blocked activation of the HER2 pathway in SK‐BR‐3 cells, compared with monotherapy. In addition, we established a model of acquired resistance to lapatinib by chronically challenging SK‐BR‐3 breast cancer cells with increasing concentrations of lapatinib. Here, we showed that bortezomib notably induced apoptosis of lapatinib‐resistant SK‐BR‐3 pools and further inhibited HER2 signaling in the resistant cells. Taken together, the current data indicate a synergistic interaction between lapatinib and bortezomib in HER2‐overexpressing breast cancer cells and provide the rationale for the clinical evaluation of these two noncross‐resistant targeted therapies. The combination of lapatinib and bortezomib may be a potentially novel approach to prevent or delay the onset of acquired resistance to lapatinib in HER2‐overxpressing/estrogen receptor (ER)‐negative breast cancers. (Cancer Sci 2010); 00: 000–000     

Lapatinib: A Sword With Two Edges

Lapatinib is an oral dual tyrosine kinase inhibitor targeting EGFR1 and EGFR2 (HER2). Phase I trials have shown that lapatinib is well tolerated, with mild diarrhea and skin rush as common adverse effects, and low cardiotoxicity. Phase II and III trials provided evidences on clinical effectiveness in advanced or metastatic breast cancer and potential against brain metastases. Lapatinib is active in combination with trastuzumab and in trastuzumab-resistant patients, moreover it has synergistic action with capecitabine. Several clinical trials are in progress to explore the effectiveness of lapatinib in other combinations and against several tumor types.     

拉帕替尼和紫杉醇在食管癌细胞中的抗肿瘤活性及其作用机制

目的 探讨拉帕替尼、紫杉醇和拉帕替尼联合紫杉醇对食管癌EC109细胞的抗肿瘤活性及作用机制.方法 MTT法检测拉帕替尼(1、2、4、8μmol/L)、紫杉醇(5、10、20、40μg/L)及联合使用对食管癌EC109细胞增殖的影响;分别检测拉帕替尼2μmol/L、紫杉醇10μg/L及联合使用对EC109细胞的侵袭、周期...     

Promises borne out in clinical studies

This article reviews lapatinib clinical trials in patients with HER2 (ErbB2)-positive breast cancer, and is a report of a presentation from a symposium at the ECCO 14 congress in 2007.Promising clinical results have been achieved to date with lapatinib, an oral, intracellular, dual-targeted small molecule inhibitor of EGFR (ErbB1) and HER2 in patients with HER2-positive metastatic breast cancer. Lapatinib has shown impressive activity in HER2-positive metastatic breast cancer, both first-line and in heavily pretreated patients whose disease has progressed following prior treatment in the metastatic setting with taxanes, anthracyclines and trastuzumab. Lapatinib has also demonstrated activity in inflammatory breast cancer, a particularly aggressive form of the disease. Lapatinib is generally well tolerated, with the most common adverse events being diarrhoea and rash, which can be effectively managed with proactive guidelines.In conclusion, these data demonstrate that lapatinib is a promising new agent in the fight against HER2-positive breast cancer.     

Lapatinib plus letrozole for postmenopausal patients with advanced HER2+/HR+ breast cancer

Lapatinib is an oral, small-molecule dual inhibitor of human EGF receptor 1 (EGFR/erbB1) and 2 (HER2/erbB2). Lapatinib has recently been approved, in combination with capecitabine, for the treatment of HER2-positive metastatic breast cancer patients failing trastuzumab therapy. Data from clinical trials are consistently showing the key role of this agent in the management of HER2-positive disease. Moreover, interesting data are suggesting a key role of lapatinib in enhancing endocrine responsiveness and/or restoring endocrine sensitivity in hormone receptor-positive disease. The present article will summarize the main data leading to the clinical development of the combination of lapatinib and the aromatase inhibitor letrozole.     

Tykerb for breast cancer

There are four members of the ErbB family: the epidermal growth factor(EGF)receptor(also called HER1 or EGFR), HER2, HER3 and HER4. Dimerization is the process whereby two HER receptor molecules associate to form a noncovalent complex. HER dimers are the active receptor forms required for transmission of external stimuli to the interior of the cell. HER dimerization occurs upon ligand binding and both HER homodimers and heterodimers can be formed in the process. However, HER2 appears to be the preferred dimerization partner of the other HER family members. Fifteen～20% of all breast cancers are HER2 positive and have a poor prognosis. Trastuzumab is an excellent, rationally-designed targeted cancer treatment. It is a recombinant, humanized, anti-HER2 monoclonal antibody that specifically binds to the extracellular area of HER2. However, the overall trastuzumab response rate is low, and the causes of trastuzumab resistance are poorly understood. Thus, there is a need for alternative anti-HER2 strategies for trastuzumab-resistant disease. Lapatinib is an orally administered small-molecule, reversible inhibitor of both EGFR and HER2 tyrosine kinase, and its activities include subsequent inhibition of its down- stream MAPK-ERK1/2, and the AKT signaling pathway. Lapatinib is more active when used in combination with capecitabine. For women with trastuzumab pre-treated HER2-positive breast cancer, Here, I will review the basics of EGFR and HER, and the treatment strategy for HER2-positive breast cancer with lapatinib.     

Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines

Lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of Lapatinib for therapy of ESCC patients, we evaluated the effect of Lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of Lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally, the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated. Lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. Lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of Lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of Lapatinib. Cumulatively, the data indicate that Lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of Lapatinib and Cetuximab/Herceptin is a promising strategy in ESCC.