Interferon-alpha promotes the anti-proliferative effect of Erlotinib (OSI-774) on human colon cancer cell lines

Interferon-alpha (IFNalpha) treatment is associated with up-regulation of epidermal growth factor receptor (HER1/EGFR) expression and marked growth inhibition while maintaining the sensitivity of the target colon cancer cells to epidermal growth factor (Gut 2004;53:123). We aimed to determine the effect of combining IFNalpha and Erlotinib (an HER1/EGFR inhibitor) on colon cancer cell line growth. Crystal-violet staining and flow cytometry were used to assess cell proliferation and expression of HER1/EGFR. IFNalpha pre-treatment followed by a combination of IFNalpha plus Erlotinib significantly enhanced the sensitivity of 7/9 of colon cancer cell lines by 7-43%. This approach may have clinical implications for improving treatment based on targeting of HER1/EGFR.     

The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer

Small-molecule tyrosine kinase inhibitors (TKIs) of the human epidermal growth factor receptor (HER) include the reversible epidermal growth factor receptor (EGFR/HER-1) inhibitors gefitinib and erlotinib. EGFR TKIs have demonstrated activity in the treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations; however, multiple mechanisms of resistance limit the benefit of these drugs. Although resistance to EGFR TKIs can be intrinsic and correlated with molecular lesions such as in Kirsten rat sarcoma viral oncogene homolog (KRAS; generally observed in a wild-type EGFR background), acquired resistance to EGFR TKIs can evolve in the setting of activating EGFR mutations, such as in the case of EGFR T790M mutations. Several irreversible inhibitors that target multiple members of the HER family simultaneously are currently in clinical development for NSCLC and may have a role in the treatment of TKI-sensitive and TKI-resistant disease. These include PF00299804, an inhibitor of EGFR/HER-1, HER-2, and HER-4, and afatinib (BIBW 2992), an inhibitor of EGFR/HER-1, HER-2, and HER-4. Results of large, randomized trials of these agents may help to determine their potential for the treatment of NSCLC.     

The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer

Aromatase inhibitors (AIs) are an effective therapy in treating estrogen receptor-positive breast cancer. Nonetheless, a significant percentage of patients either do not respond or become resistant to AIs. Decreased dependence on ER-signaling and increased dependence on growth factor receptor signaling pathways, particularly human epidermal growth factor receptor 2 (EGFR2/HER2), have been implicated in AI resistance. However, the role of growth factor signaling remains unclear. This current study investigates the possibility that signaling either through HER2 alone or through interplay between epidermal growth factor receptor 1 (EGFR/HER1) and HER2 mediates AI resistance by increasing the tumor initiating cell (TIC) subpopulation in AI-resistant cells via regulation of stem cell markers, such as breast cancer resistance protein (BCRP). TICs and BCRP are both known to be involved in drug resistance. Results from in vitro analyses of AI-resistant versus AI-sensitive cells and HER2-versus HER2+ cells, as well as from in vivo xenograft tumors, indicate that (1) AI-resistant cells overexpress both HER2 and BCRP and exhibit increased TIC characteristics compared to AI-sensitive cells; (2) inhibition of HER2 and/or BCRP decrease TIC characteristics in letrozole-resistant cells; and (3) HER2 and its dimerization partner EGFR/HER1 are involved in the regulation of BCRP. Overall, these results suggest that reducing or eliminating the TIC subpopulation with agents that target BCRP, HER2, EGFR/HER1, and/or their downstream kinase pathways could be effective in preventing and/or treating acquired AI resistance.     

Preclinical antitumor activity of S‐222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are validated molecular targets in cancer therapy. Dual blockade has been explored and one such agent, lapatinib, is in clinical practice but with modest activity. Through chemical screening, we discovered a novel EGFR and HER2 inhibitor, S‐222611, that selectively inhibited both kinases with IC₅₀s below 10 nmol/L. S‐222611 also inhibited intracellular kinase activity and the growth of EGFR‐expressing and HER2‐expressing cancer cells. In addition, S‐222611 showed potent antitumor activity over lapatinib in a variety of xenograft models. In evaluations with two patient‐oriented models, the intrafemoral implantation model and the intracranial implantation model, S‐222611 exhibited excellent activity and could be effective against bone and brain metastasis. Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S‐222611 showed equivalent or slightly weaker antitumor activity but a safer profile. These results indicated that S‐222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses. Considering the safer profile than for irreversible inhibitors, S‐222611 could be an important option in future cancer therapy.     

Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells

One of the major targets for breast cancer therapy is the epidermal growth factor receptor (EGFR) and related receptors, which signal via different signal transduction pathways including the mitogen-activated protein kinase (MAPK) pathway. This study determined whether there is a correlation between EGFR/HER2 status and MAPK (ERK1/2) phosphorylation in breast cancer cells, and how this affects the response to an inhibitor of the receptors. Expression of EGFR, HER2 and phosphorylated ERK1/2 were measured by immunoblotting in a panel of breast cancer cell lines. Several lines expressed high levels of pERK1/2, with no obvious correlation with the level of EGFR/HER2. The EGFR tyrosine kinase inhibitor PKI166 inhibited growth and induced apoptosis in some cells with high levels of growth factor receptors (MDA-MB-468, SUM149, SKBR3), but was less effective in cells that also had high basal ERK1/2 activity (MDA-MB-231). The combination of an inhibitor of MAPK signalling (U0126) and PKI166 produced significantly more inhibition and apoptosis than either agent alone. This suggests that constitutive activation of the MAPK pathway may bypass inhibition of EGFR/HER2 tyrosine kinases, and lead to insensitivity to agents targeting the receptors. However, inhibiting both EGFR/HER2 and MAPK signalling can result in significant growth inhibition and apoptosis of EGFR-expressing breast cancer cells.     

Small cell lung cancer cells express EGFR and tyrosine phosphorylation of EGFR is inhibited by gefitinib ("Iressa", ZD1839)

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839) has demonstrated anti-tumor activity in non-small cell lung cancer (NSCLC) and has been approved in over 20 countries. NSCLC has been reported to express high levels of EGFR. However, gefitinib appears to be more effective against adenocarcinoma than squamous cell carcinoma, the latter expressing more EGFR. In the present study, we evaluated the effect of gefitinib against the small cell lung cancer (SCLC) cell lines NCI-H82, NCI-H209, NCI-H510, NCI-H526 and NCI-H660. SCLC has been reported to express a low to undetectable level of EGFR. We compared the effects of gefitinib between cell lines with detectable and undetectable EGFR expression. First, we evaluated expression levels of EGFR and HER2/neu by Western blotting and immunoprecipitation respectively; EGFR protein was detected in two of the five SCLC cell lines, whereas HER2/neu was not detected in any. Next, we analyzed expression levels of phosphorylated ERK1/2 and compared these results with EGFR (HER-1/ErbB1) and HER2/neu (ErbB2) expression levels, as EGFR conducts signals through Ras-Raf-MAPK pathway; gefitinib inhibited phosphorylation of ERK1/2 by EGF addition in cell lines with detectable and undetectable EGFR expression. These data suggest that gefitinib is potentially effective against cancers with low EGFR expression such as SCLC.     

Therapeutic targeting of the epidermal growth factor receptor in human cancer

The epidermal growth factor receptor (EGFR; also referred to as HER1 or ERBB1), is a member of the type 1 receptor tyrosine kinase family known as the ERBB family. Comprising 4 members-ERBB1, ERBB2 (also known as HER2), ERBB3 (HER3), and ERBB4 (HER4)-these receptors play a principal role in allowing cells to integrate and respond correctly to diverse external stimuli, ranging from soluble endocrine and paracrine factors to signaling molecules on neighboring cells. The cell must interpret these extracellular signals to produce an appropriate developmental or proliferative response, and aberrant activation of the kinase activity of these receptors, particularly EGFR and ERBB2, is important in the development and progression of human cancer. Given its roles in signal transduction and development of the malignant phenotype, EGFR has emerged as a critical target for therapeutic development against various forms of cancer. This review focuses on the current therapeutic approaches directed against EGFR, the emerging challenges of EGFR therapy resistance, and how our increasing knowledge of EGFR biology is driving more targeted or alternative approaches to cancer therapies.     

Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas

Erlotinib (Tarceva) is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor initially approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine (Gemzar) in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. Physicians and patients now have a new option for the treatment of locally advanced/metastatic adenocarcinoma of the pancreas.     

Pan‐HER—An antibody mixture targeting EGFR,HER2 and HER3 abrogates preformed and ligand‐induced EGFR homo‐ and heterodimers

The human epidermal growth factor receptor (HER)‐family is involved in development of many epithelial cancers. Therefore, HER‐family members constitute important targets for anti‐cancer therapeutics such as monoclonal antibodies (mAbs). A limitation to the success of single HER‐targeting mAbs is development of acquired resistance through mechanisms such as alterted receptor dimerization patterns and dependencies. Pan‐HER is a mixture of six mAbs simultaneously targeting epidermal growth factor receptor (EGFR), HER2 and HER3 with two mAbs against each receptor. Pan‐HER has previously demonstrated broader efficacy than targeting single or dual receptor combinations also in resistant settings. In light of this broad efficacy, we decided to investigate the effect of Pan‐HER compared with single HER‐targeting with single and dual mAbs on HER‐family cross‐talk and dimerization focusing on EGFR. The effect of Pan‐HER on cell proliferation and HER‐family receptor degradation was superior to treatment with single mAbs targeting either single receptor, and similar to targeting a single receptor with two non‐overlapping antibodies. Furthermore, changes in EGFR‐dimerization patterns after treatment with Pan‐HER were investigated by in situ proximity ligation assay and co‐immunoprecipitation, demonstrating that Pan‐HER and the EGFR‐targeting mAb mixture efficiently down‐regulate basal EGFR homo‐ and heterodimerization in two tested cell lines, whereas single mAbs had limited effects. Pan‐HER and the EGFR‐targeting mAb mixture also blocked EGF‐binding and thereby ligand‐induced changes in EGFR‐dimerization levels. These results suggest that Pan‐HER reduces the cellular capability to switch HER‐dependency and dimerization pattern in response to treatment and thus hold promise for future clinical development of Pan‐HER in resistant settings.     

Co-Treatment with Panitumumab and Trastuzumab Augments Response to the MEK Inhibitor Trametinib in a Patient-Derived Xenograft Model of Pancreatic Cancer

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and epidermal growth factor receptor (EGFR) family signaling are drivers of tumorigenesis in pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated that combinatorial treatment of PDAC xenografts with the mitogen-activated protein kinase–extracellular-signal-regulated kinase (ERK) kinase1/2 (MEK1/2) inhibitor trametinib and the dual EGFR/human epidermal growth factor receptor 2 (HER2) inhibitor lapatinib provided more effective inhibition than either treatment alone. In this study, we have used the therapeutic antibodies, panitumumab (specific for EGFR) and trastuzumab (specific for HER2), to probe the role of EGFR and HER2 signaling in the proliferation of patient-derived xenograft (PDX) tumors. We show that dual anti-EGFR and anti-HER2 therapy significantly augmented the growth inhibitory effects of the MEK1/2 inhibitor trametinib in three different PDX tumors. While significant growth inhibition was observed in both KRAS mutant xenograft groups receiving trametinib and dual antibody therapy (tumors 366 and 608), tumor regression was observed in the KRAS wild-type xenografts (tumor 738) treated in the same manner. Dual antibody therapy in conjunction with trametinib was equally or more effective at inhibiting tumor growth and with lower apparent toxicity than trametinib plus lapatinib. Together, these studies provide further support for a role for EGFR and HER2 in pancreatic cancer proliferation and underscore the importance of therapeutic intervention in both the KRAS–rapidly accelerated fibrosarcoma kinase (RAF)–MEK–ERK and EGFR-HER2 pathways to achieve maximal therapeutic efficacy in patients.Abbreviations: EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; FDA, Food and Drug Administration; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma viral oncogene homolog; MEK1/2, mitogen-activated protein kinase–ERK kinase1/2; PDAC, pancreatic ductal adenocarcinoma; PDX, patient-derived xenograft; pEGFR, phospho-EGFR; pHER2, phospho-HER2; pJNK, phospho–c-Jun N-terminal kinase; pRTK, phospho–receptor tyrosine kinase; RAF, rapidly accelerated fibrosarcoma kinase; Tra + P + T, trametinib plus panitumumab plus trastuzumab     

Estrogen receptor-negative and human epidermal growth factor receptor 2-negative breast cancer tissue have the highest Ki-67 labeling index and EGFR expression: gene amplification does not contribute to EGFR expression

Estrogen receptor (ER) and human epidermal growth factor 2 (HER2) are well-investigated molecules and the focus of many breast cancer therapies. There is a group of breast cancers lacking ER and HER2, but it is not fully understood. Treatment for these patients is limited to cytotoxic chemotherapy. The purpose of present study is to examine ER(-)/HER2(-) breast cancers, with a particular focus on epidermal growth factor receptor (EGFR). EGFR is a target molecule for which novel medicines have been recently developed for other organ cancers, however biological significance in breast cancer is not yet well demonstrated. Breast cancer specimens (n=58) were categorized into four groups: i) ER(+)/HER2(-) (51.7%); ii) ER(+)/HER2(+) (8.6%); iii) ER(-)/HER2(+) (20.7%); and iv) ER(-)/HER2(-) (19.0%). They were immunohistochemically (IHC) examined using antibodies for EGFR, platelet derived growth factor receptor (PDGFR)alpha, PDGFRbeta, parathyroid hormone (PTH) receptor, Ki-67, cyclinD1, p53, and vimentin. The Ki-67 labeling index (LI) was highest in ER(-)/HER2(-) (36.5%), and decreased in order from ER(-)/HER2(+) (31.4%), ER(+)/HER2(+) (17.7%), to (ER(+)/HER2(-) (15.9%) (p=0.001). EGFR, p53 and vimentin were highly expressed in ER(-)/HER2(-) breast cancer cells (p<0.01). CyclinD1 was inversely expressed to Ki-67 LI (p<0.001). Gene amplification of EGFR was examined by two in situ hybridization techniques, fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) in serial sections to IHC. Only 1 of 14 EGFR-positive breast cancers showed gene amplification at low levels by CISH. Overall, the ER(-)/HER2(-) breast cancer showed the highest Ki-67 LI, the most frequent expression of EGFR, p53 and vimentin, as well as the lowest expression of cyclinD1. It is unlikely that gene amplification contributes to EGFR expression. ER(-)/HER2(-) breast cancers have potential in the development of novel therapeutics, including targeted medicines.     

ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells.

PURPOSE: ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. EXPERIMENTAL DESIGN: We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. RESULTS: ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro, and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. CONCLUSIONS: ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors.     

MP470, a novel receptor tyrosine kinase inhibitor, in combination with Erlotinib inhibits the HER family/PI3K/Akt pathway and tumor growth in prostate cancer

Background  

Prostate cancer is a common disease in men and at present there is no effective therapy available due to its recurrence despite androgen deprivation therapy. The epidermal growth factor receptor family (EGFR/HER1, HER2/neu and HER3)/PI3K/Akt signaling axis has been implicated in prostate cancer development and progression. However, Erlotinib, an EGFR tyrosine kinase inhibitor, has less effect on proliferation and apoptosis in prostate cancer cell lines. In this study, we evaluate whether MP470, a novel receptor tyrosine kinase inhibitor alone or in combination with Erlotinib has inhibitory effect on prostate cancer in vitro and in vivo.     

Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/AKT signaling pathway in breast cancer cells

Survivin, a member of the inhibitor of apoptosis protein family, is widely expressed in a variety of human cancer tissues. Survivin inhibits activation of caspases, and its overexpression can lead to resistance to apoptotic stimuli. In this study, survivin protein expression was assessed by immunohistochemical staining of 195 invasive breast cancer specimens. Overall, 79.5% of the tumors were positive for survivin. The expression of epidermal growth factor receptor (EGFR) family, human epidermal growth factor receptor 2 (HER2) and EGFR, was also examined in 53 cases, and consequently, it was indicated that survivin positivity might be correlated with the coexpression of HER2 and EGFR. To clarify the regulatory mechanism of survivin expression in breast cancer cells, the effect of HER2 and/or EGFR expression on the survivin levels was examined. It was revealed that the survivin protein level was up-regulated by the coexpression of HER2 and EGFR, leading to the increased resistance against etoposide-induced apoptosis in breast cancer cells. Conversely, survivin levels and apoptosis resistance were decreased when cells were treated with HER2-specific inhibitor, Herceptin. Although Herceptin could down-regulate both phosphatidylinositol 3-kinase (PI3K)/AKT signal and mitogen-activated protein/extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signal in HER2-positive breast cancer cells, PI3K-specific inhibitor but not MEK1-specific inhibitor could decrease the survivin levels. The present study clarified the regulatory mechanism of HER2 in the expression of survivin protein in breast cancer cells.     

Enhanced sensitivity to the HER1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib hydrochloride in chemotherapy-resistant tumor cell lines.

PURPOSE: Erlotinib (Tarceva, OSI-774) is a potent and specific inhibitor of the HER1/epidermal growth factor receptor (EGFR) tyrosine kinase. In phase II clinical studies, oral erlotinib monotherapy has shown antitumor activity in patients with advanced non-small cell lung cancer, head and neck cancer, and ovarian cancer after the failure of standard chemotherapy. We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the HER1/EGFR signaling pathways for survival. EXPERIMENTAL DESIGN: The growth-inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive, parental, and chemoresistant tumor cell lines. RESULTS: Enhanced sensitivity to erlotinib was observed in the doxorubicin-resistant human breast cancer cell line MCF-7, paclitaxel-resistant human ovarian carcinoma cell line A2780, and cisplatin-resistant human cervical carcinoma cell line ME180. The IC(50) values of erlotinib in the resistant cell lines were 2- to 20-fold lower than those in the corresponding parental cell lines. This enhanced sensitivity to erlotinib correlated with higher HER1/EGFR and phospho-HER1/EGFR expression when compared with the corresponding parental cell lines. Acquired resistance to cytotoxic agents was not associated with cross-resistance to erlotinib. AE-ME180/CDDP-resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did. CONCLUSIONS: Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to HER1/EGFR inhibitors, which correlates with increased HER1/EGFR expression. These data may explain some of the observed clinical activity of HER1/EGFR inhibitors in patients previously treated with multiple therapies. HER1/EGFR tyrosine kinase inhibitors may be more effective as second- or third-line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens.     

Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway

A humanized anti-HER2 monoclonal antibody pertuzumab (Omnitarg, 2C4), binding to a different HER2 epitope than trastuzumab, is known as an inhibitor of heterodimerization of the HER receptors. Potent antitumor activity against HER2-expressing breast and prostate cancer cell lines has been clarified, but this potential is not clear against lung cancers. The authors investigated the in vitro anti-tumor activity of pertuzumab against eight non-small cell lung cancer cells expressing various members of the HER receptors. A lung cancer 11_18 cell line expressed a large amount of HER2 and HER3, and its cell growth was stimulated by an HER3 ligand, heregulin (HRG)-alpha. Pertuzumab significantly inhibited the HRG-alpha-stimulated cellular growth of the 11_18 cells. Pertuzumab blocked HRG-alpha-stimulated phosphorylation of HER3, mitogen-activated protein kinase (MAPK), and Akt. In contrast, pertuzumab failed to block epidermal growth factor (EGF)-stimulated phosphorylation of EGF receptor (EGFR) and MAPK. Immunoprecipitation showed that pertuzumab inhibited HRG-alpha-stimulated HER2/HER3 heterodimer formation. HRG-alpha-stimulated HER3 phosphorylation was also observed in the PC-9 cells co-overexpressing EGFR, HER2, and HER3, but the cell growth was neither stimulated by HRG-alpha nor inhibited by pertuzumab. The present results suggest that pertuzumab is effective against HRG-alpha-dependent cell growth in lung cancer cells through inhibition of HRG-alpha-stimulated HER2/HER3 signaling.     

EGFR,HER2和HER3在胆管癌中的表达及预后价值

目的 观察表皮生长因子受体(Epidermal growth factor receptor,EGFR)、表皮生长因子受体2(Human epidermal growth factor receptor 2,HER2)和表皮生长因子受体3(Human epidermal growth factor receptor 3,HER3)在胆管癌(Cholangiocarcinoma,CCA)组织中的表达情况,探讨其与CCA患者临床病理特征、总生存期和CCA细胞增殖的关系。方法 收集2009年1月—2013年10月于我院手术的CCA患者50例,并同时收取癌旁组织作为对照。采用免疫组织化学方法及RT-PCR方法检测CCA及癌旁组织中EGFR、HER2和HER3表达情况。收集患者临床病理参数,分析EGFR、HER2和HER3表达与CCA临床病理参数之间的关系。绘制Kaplan-Meier生存曲线,采用Log-rank检验和Cox比例风险模型分析EGFR、HER2和HER3表达情况与50例CCA患者术后总生存期之间的关系。采用RNA干扰方法敲低CCA细胞株QBC939中EGFR、HER2和HER3表达,Western blot检测EGFR、HER2和HER3敲低效果,MTT方法检测EGFR、HER2和HER3对QBC939细胞增殖的影响。结果 CCA组织中可检测到EGFR、HER2和HER3的阳性表达。临床病理特征关系分析结果显示,HER2表达与CCA淋巴结转移相关(P＜0.05);而EGFR和HER3除与CCA淋巴结转移相关外,还与肿瘤分化程度相关(P＜0.05)。EGFR、HER2和HER3阳性患者术后总生存期明显低于阴性患者(P＜0.05)。敲低CCA QBC939细胞中EGFR、HER2和HER3表达后,QBC939细胞增殖能力显著降低(P＜0.05)。结论 CCA组织中EGFR、HER2和HER3表达与患者总生存期密切相关,机制可能与促进CCA细胞的增殖相关。     

Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib,lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence

An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.     

Interferon-alpha promotes the anti-proliferative effect of gefitinib (ZD 1839) on human colon cancer cell lines

OBJECTIVE: Interferon-alpha (IFN alpha) treatment is associated with up-regulation of epidermal growth factor receptor (HER 1/EGFR) expression and marked growth inhibition of colon cancer cell lines in vitro.We aimed to determine the effect of combining IFN alpha and gefitinib on colon cancer cell line growth. METHODS: A panel of nine colon cancer cell lines were characterised for expression of HER 1/EGFR and then treated with gefitinib alone, or IFN alpha alone, or IFN alpha plus gefitinib, following a pre-treatment using vehicle or IFN alpha. Crystal violet staining and flow cytometry were used to assess cell proliferation and expression of HER 1/EGFR. The indexes and statistical assays were used to evaluate significant differences between treatment groups against vehicle control. RESULTS: All cell lines except SW 620 were HER 1/EGFR positive. IFN alpha treatment was associated with significant up-regulation of cell surface HER 1/EGFR expression in all HER 1/EGFR-positive cell lines except KM 12 SM. Concurrent treatment with IFN alpha and gefitinib, or IFN alpha pre-treatment followed by gefitinib, or IFN alpha pre-treatment followed by a combination of IFN alpha plus gefitinib, additively or supra-additively/synergistically enhanced the sensitivity of the seven HER 1/EGFR-up-regulated cell lines. CONCLUSION: IFN alpha improves the anti-proliferative effect of EGFR inhibition in colorectal cancer cell lines. This approach may have clinical implications for improving treatment based on targeting of HER 1/EGFR.