Human Epidermal Receptor Family Research Articles

Abstract P1-04-17: Clinical and pathological differences between HER2 Low and other cancer subtypes in breast cancer patients

Abstract Background: HER2 is a tyrosine kinase receptor belonging to the human epidermal receptor family and is considered an important proto-oncogene in the biology of breast carcinoma. HER2 overexpression is determined by a +3 score on the immunohistochemistry (IHC) assay. In addition, tumors with IHC results of +1 or +2 with ISH negative were defined as HER2-low. Recent studies have shown that the clinicopathological characteristics of HER2-low tumors, pointing out potential differences regarding hormone receptor status and new treatment possibilities in this patients. Objective: To assess the frequency and clinicopathological differences between cancer subtypes, as well as the survival of these patients. Methods: All patients with breast cancer diagnosed between 1987 and 2021 included in the Pérola Byington Hospital database were eligible. Patients were excluded if they had bilateral disease, had participated in clinical studies, or had incomplete data. The primary endpoint was overall survival stratified by cancer subtype, secondary endpoints were clinicopathological differences between cancer subtypes and death probability. Both the t-test and the chi-square test were used to analyze the association of each variable between the groups. Multivariate analysis was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the death outcome. Cox regression was used for survival analysis, with the Log-rank method and the results were presented in a survival graph using the Kaplan-Meier method. The R software version 4.1.1 was used to perform all analyzes, with a p-value < 0.05 being considered statistically significant. Results: 11,234 patients were included: 4,541 (40.42%) had Luminal cancer subtype, 2,955 (26.30%) HER2 Low, 2,242 (19.96%) triple negative, and 1,496 (13.32%) HER2 overexpression. Age, self-reported ethnicity, BMI, presence of comorbidities, clinical stage, nuclear grade, histological grade, family history, radiotherapy, chemotherapy, surgery, local, and systemic recurrence, and death showed statistically significant differences between cancer subtypes (table 1). In the multivariate regression (adjusted for the other evaluated characteristics), patients with HER2 overexpression cancer subtype showed a 44.8% greater probability of death than patients with HER2 Low (OR 1.448, 95%CI 1.046-2.004, p=0.026), while the patient with triple-negative cancer had a 26.1% lower probability of evolving to death when compared to the HER2 Low patient (OR 0.739, 95%CI 0.562-0.969, p=0.0229). The luminal subtype showed no statistically significant difference when compared to the patient with HER2 Low. Overall survival showed a statistically significant difference between cancer subtypes, with a median of 12 years for Luminal HR 0.816 (0.73-0.913), 15 years for HER2 overexpression HR 1.154 (1.003-, 327), and no statistical difference for triple negative HR 0.978 (0.859-1.114) compared to 12 years for HER2 Low. Conclusion: This study in breast cancer patients demonstrates significant differences between cancer subtypes, with a higher probability of progression to death for patients with HER2 overexpression, while patients with Luminal subtype had a lower probability, when compared with HER2 Low. More studies are needed to clarify the impact of these differences between cancer subtypes on response to therapy. Association between cancer subtype and other variables (n=11,234). Citation Format: ANDRE MATTAR, Andressa Amorim, Marina Diogenes, Jorge Shida, Luiz Henrique Gebrim. Clinical and pathological differences between HER2 Low and other cancer subtypes in breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-17.

HER2-Low Breast Cancer: Prognosis and Future Treatment Prospective

The human epidermal growth factor 2 (HER2) is a tyrosine kinase belonging to the Human Epidermal Receptor family [1]. HER2 is amplified leading to HER2 overexpression in 15% of breast cancers (BC) [2]. HER2 overexpression leads to poor prognosis, but offers the unique possibility to use a targeted therapy with monoclonal antibodies. This therapeutic option has radically changed the history of HER2 BC [3]. HER2 overexpression represents at present the most powerful predictive factor for likeliness of response to anti-HER2 agents [5]. The HER2 status is routinely assessed either using immunohistochemistry (HER2 protein expression level) or in situ hybridization (HER2 gene status) [2,5,6]. For the purpose of HER2 assessment, international guidelines have been developed by experts in the field, and have changed over the years according to new data. HER2 heterogeneity is linked to the complexity of equivocal results, HER2 mutations and the upcoming category of HER2-low BC [7]. Intratumor genetic heterogeneity interests various types of human cancers, including BC and HER2 overexpression and amplification, and it is demonstrated to be significantly more common in cases with HER2 equivocal status [8]. Equivocal cases frequently feature low levels of HER2 amplification. Several studies showed that HER2 heterogeneity is related to poor outcome, shorter disease-free survival and overall survival. Patients with HER2 heterogeneity are less responsive to target therapies as confirmed by a lower achievement of pathologic complete response following neoadjuvant treatment [9]. In spite of the scarcity of data still available on HER2-low BC, different intrinsic subtypes seem to influence different clinical behavior and response to treatment, as this has already been proved for other BC subtypes. HER2-low/HR- BC showed a higher frequency of HER2-enriched instrinsic subtype than HER2-/HR- BC. This might mean that, despite in clinical practice HER2-low/HR- BC is considered as HER2-/HR, these subtypes of BCs might reflect a different clinical behavior and a different response to targeted therapy [10]. Recent studies underlined that HER2-enriched instrinsic subtype are the most beneficial in reduction of risk of progression and death after CDK6/6-inhibitors treatment, compared to the other subtypes [11]. Traditionally HER2-positive BCs were separated from HER2-negative BCs, based on solid clinical data stating that only tumors driven by HER2 oncogene addition benefit from targeted therapies [12]. However in recent years new therapies have been developed, in particular the antibody drug conjugates which deliver chemotherapy inside the BC. Some of these agents - such as trastuzumab duocarmazine and trastuzumab deruxtecan showed encouraging response rates also in the so called HER2-low BC. For example, the phase 1 study of DS-8201 showed an overall response rate of 37% in pretreated HER2-low metastatic cancer patients, with a median duration of response of 10.4 months [13]. These data suggests a paradigm shift in the definition of HER2 status, which may be based on 3 groups: 1.HER2-positive, 2.HER2- negative, 3.HER2-low BCs, that may potentially benefit from a targeted therapy, even in absence of the addition of the tumor cells to the HER2 oncogene [7]. At present there are no formal definitions of HER2-low BC, but it seems reasonable to define as HER2-low all BCs displaying a score of 1+ or 2+ HER2 expression and no HER2 amplification. This assumption would categorize up to 55% of BCs as HER2-low. For this subtype there are no targeted therapies approved [7]. The majority of HER2 somatic mutations found in BCs have not been associated with HER2 gene amplification. However preclinical data suggest that functionally active HER2 mutations may lead to HER2 targeted therapies sensitivity [14]. Other preclinical models suggest that pertuzumab inhibits tumor proliferation even in absence of HER2 overexpression [15].So, HER2 mutation-positive but HER2-negative BC may benefit from targeted drugs, but further studies are needed. For example, trastuzumab, deruxtecan, a novel enzyme-cleavable linker, showed significant objective response and disease control in a group of patients including 25% HER2-low BCs, and therefore is worthy of further studies in this subgroup of patients [16]. The new agents being tested for HER2-low BC patients are antibody drug conjugates deploying anti-HER2 epitopes in their antibody component, but with different cytotoxic warheads and a bi-specific antibody targeting both HER2 and HER3 [17]. In conclusion, the concept of HER2-positive versus HER2-negative disease is changing, including the definition of “HER2-low” BC, against which new therapies such as antibody drug conjugates may be extremely effective.

Corosolic acid inhibits colorectal cancer cells growth as a novel HER2/HER3 heterodimerization inhibitor.

Colorectal cancer is the third most common cancer worldwide. HER2 and HER3 are two members of human epidermal receptor family of tyrosine kinase receptors (RTKs) and associated with poor survival in colorectal cancer. They have been observed as important therapeutic targets in various types of cancer. Corosolic acid, a natural pentacyclic triterpene, has been demonstrated to have a significant anti-cancer activity. However, the target of corosolic acid has not yet been explored. This study aimed to reveal the direct targets of corosolic acid underlying its anti-cancer activities. The targets of corosolic acid were revealed by the phospho-RTK array, bio-layer interferometry, co-immunoprecipitation, and proximity ligation assay. The inhibitory action of corosolic acid on HER2/HER3 heterodimerization and related downstream signalling were investigated in HCT116 and SW480 cells. In addition, the chemo-preventive effects of corosolic acid were validated in both HCT116 xenograft model and AOM/DSS model. Our results demonstrated that corosolic acid could prevent NRG1-induced HER2/HER3 heterodimerization and suppress the phosphorylation of both HER2 and HER3. Furthermore, HER2 and HER3 could regulate the downstream signalling pathways of RalA/RalBP1/CDK1 and PI3K/Akt/PKA, respectively, resulting in the changes in phosphorylation of Drp1 and mitochondrial dynamics. corosolic acid exhibited anti-cancer activity in both HCT116 xenograft model and AOM/DSS model. Collectively, our results demonstrated corosolic acid directly targeted HER2 and HER3 heterodimerization and inhibited mitochondrial fission via regulating RalA/RalBP1/CDK1 and PI3K/Akt/PKA pathways, revealing a novel mechanism underlying the beneficial effects of corosolic acid on colorectal cancer.

Human epidermal receptor family inhibitors in patients with ERBB3 mutated cancers: Entering the back door

IntroductionTherapeutic inhibition of the human epidermal receptor 3 (ERBB3, HER3) has been challenged by the low frequency of ERBB3 somatic alterations across cancer types. We have evaluated the clinical utility to use available inhibitors of the HER family in the context of ERBB3 mutations. Patients and methodsIn this study, we have selected patients with somatic ERBB3 alterations detected in their tumours from the molecular screening programs running at our institution. Techniques used for molecular screening were targeted next generation sequencing, comparative genomic hybridisation and/or whole exome sequencing on fresh frozen tumour biopsies. ResultsOn the 844 patients with a molecular portrait of their tumours, 31 (3.7%) had a somatic mutation of ERBB3. Overall, 9 patients received available inhibitors of HER family, including trastuzumab and/or lapatinib or afatinib. Sixteen patients received other molecularly targeted agents, including the Mammalian Target Of Rapamycin (mTOR), the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PI3K) or NOTCH inhibitors or chemotherapy, and 4 patients failed being treated. Thirteen different histological subtypes were affected by ERBB3 mutations; top ones were colorectal carcinomas (6 patients), non-small cell lung cancers (4 patients, including a squamous cell carcinoma), head and neck squamous cell carcinomas (3 patients) and breast carcinomas (3 patients). The presence of a mutation in the tyrosine kinase domain of the ERBB3/HER3 protein detected in four patients' tumours was significantly related to good progression-free survival (hazard ratio [HR] = 0.18, p value = 0.022) and overall survival (HR = 0.19, p value = 0.03) in univariate analysis. Treatment of these four patients included at least a tyrosine kinase inhibitor lapatinib or afatinib. ConclusionOur exploratory analysis suggests that mutations in the tyrosine kinase domain of the HER3 protein are related to a favourable outcome under HER family inhibitors.

Los receptores epidérmicos humanos en el cáncer gástrico: alteraciones moleculares y su papel como diana terapéutica.

Gastric cancer (GC) is the third leading cause of cancer death worldwide; both environmental and genetic factors are involved in the etiology of this neoplasia. The human epidermal receptor (HER) pathway is essential for proliferation and differentiation of normal cells; but it is also implicated in the growth of cancer cells. In this work we investigate the molecular alterations in genes that encodes for HER receptors reported in GC, as well the role as therapeutic targets. We reviewed the literature reported to date regarding overexpression of HER-receptors, amplification and somatic mutations in ERBB genes occurred in gastric tumors, as well as the anti-HER therapies tested for treatment of GC. In GC, the overexpression of HER family is reported in a range of 12-87% of cases; up to 67% of cases with amplification, and 90 somatic mutations in ERBB genes. The only drug anti-HER approved for using combined with chemotherapy, in treatment of patients with advanced GC is trastuzumab; however, other targeted therapies are being investigated. The role of the HER family as a therapeutic target has not shown significant improvements in recent years; hence, further studies are required to find better options for treatment of GC.

Production and Characterization of Monoclonal Antibodies Against the Dimerization Domain of Human HER2

Background: Human Epidermal Growth factor Receptor 2 (HER2), also known as ErbB2 is a 185 kDa protein belonging to the Human Epidermal Receptor (HER) family of tyrosine kinase receptors overexpressed in 20% - 30% of patients with breast cancer. Similar to other members of the HER family, HER2 glycoprotein comprises of multiple domains including an extracellular ligand-binding domain, a single transmembrane domain and a cytoplasmic domain with tyrosine kinase activity. The extracellular domain of HER2 with 632 amino acids is composed of four subdomains (I - IV); subdomains I and III form a ligand binding site, and cysteine-rich subdomains II and IV play an important role in dimerization of the receptor. Materials and Methods: Primarily, BALB/c mice were immunized with a 30-aminoacid peptide as a part of the human HER2 subdomain II. Splenocytes from hyperimmunized mice were fused with myeloma cells (SP2/0), selected in hypoxanthine-aminopterin-thymidine (HAT) medium, and screened by indirect Enzyme-Linked Immunosorbent Assay (ELISA). Secreted MAbs were characterized according to isotypes, reactions with the native HER2 in SKBR3 cells by western blotting, and in tissue sections from HER2 positive breast cancer specimens by Immunohistochemistry (IHC). Conclusions: The results of both western blotting and Immunohistochemistry showed that native HER2 can be detected with 1F1 monoclonal antibody.

Role of HER Family Members in Predicting Prognoses in Epithelial Ovarian Cancer: A Meta-analysis

Human epidermal receptor (HER) family receptors are commonly overexpressed in various human tumors, and their overexpression is thought to play a critical role in tumor progression. The aim of this meta-analysis was to evaluate the prognostic significance of HER family members in epithelial ovarian cancer (EOC). Relevant studies published between January 1, 1980, and April 24, 2013, that evaluated the associations of HER family members with overall survival (OS), progression-free survival (PFS), response to platinum-based chemotherapy, lymph node metastasis, or ascites in EOC were identified via searches of PubMed and EMBASE. We identified 37 eligible articles that met the inclusion criteria. The results of the meta-analysis revealed that significantly poorer OS of patients with EOC was predicted by high Her-2 expression levels (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.31-2.19). Furthermore, high Her-2 expression was significantly associated with poor PFS (HR 1.88, 95% CI 1.46-2.41) and an increased risk of ascites (risk ratio 1.21, 95% CI 1.02-1.42). High levels of expression of Her-2 are significantly related to poor survival and an increased risk of ascites in patients with EOC. Future prospective cohorts with larger samples are needed to verify the prognostic value of Her-2 expression in EOC.

Co-Expression of HER Family Members in Patients with Dukes’ C and D Colon Cancer and Their Impacts on Patient Prognosis and Survival

The human epidermal growth factor receptor (EGFR) is an important therapeutic target in patients with metastatic colorectal cancer and anti-EGFR antibodies cetuximab and panitumumab have been approved for the treatment of such patients. Despite these advances, the duration of response in some patients can be limited. Since, EGFR is capable of forming heterodimers with the other members of the HER (Human epidermal receptor) family, it is important to investigate the co-expression and prognostic significance of all members of the HER family in colorectal cancer patients. The expression of the HER family members were determined in tumour specimens from 86 patients with Dukes’ C and D (metastatic) colon cancer using immunohistochemistry. Sections were scored by the percentage of positive tumour cells and intensity of staining. Their associations with clinicopathological parameters, and overall survival and disease free survival were evaluated using univariate and multivariate analysis. Overall, 43%, 77%, 52% and 92% of the cases were EGFR, HER-2, HER-3 and HER-4 positive respectively. Interestingly, 35%, 24%, 43%, and 18% of the cases had co-expression of EGFR/HER-2, EGFR/HER-3, EGFR/HER-4 and all four members of the HER family respectively. Of these, only the expression of EGFR and co-expression of EGFR/HER-4 were associated with poorer disease-free survival in both univariate and multivariate analysis. Co-expression of all members of the HER family in colon cancer supports the need for further investigations on their predictive value for response to therapy with anti-EGFR mAbs and whether such sub-population of patients may benefit from therapy with the new generation of pan-HER inhibitors.

EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy

Background:Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy.Methods:We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition.Results:Among several predicted peptide epitopes, EGFR875–889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR875–889 epitope could be detected in the blood of HNSCC patients. EGFR875–889-reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR875–889-reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.Conclusion:We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR875–889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy.

Epidermal growth factor receptor pathway as therapeutic development in head and neck cancers: present and future

The understanding of the epidermal growth factor pathway in terms of intracellular signaling and its role in proliferation and cell survival has impacted the therapeutic management of many solid tumor malignancies in which this pathway has been dysregulated. Once the receptor is targeted at its cellular membrane level or tyrosine kinase domain, its blockage induces downregulation of oncogenic and tumorigenesis mechanisms which were in place, and thus inhibits proliferation and induces apoptosis of the malignant cell. Nowadays, we have several monoclonal antibodies as well as small molecules which target the receptor of epidermal growth factor. Although several receptors have been described within the human epidermal receptor family, our discussion will be focused on the impact of human epidermal receptor-1 as a therapeutic option for locally advanced squamous cell carcinoma of the head and neck.

Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition

BackgroundGastric cancer is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Thus, MET is considered a good candidate for targeted therapeutic intervention in this type of tumor, and MET inhibitors recently entered clinical trials. One of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. Perspective studies are thus mandatory to identify the molecular mechanisms that could cause resistance to these therapies.ResultsOur in vitro and in vivo results demonstrate that, in MET-addicted gastric cancer cells, the activation of HER (Human Epidermal Receptor) family members induces resistance to MET silencing or inhibition by PHA-665752 (a selective kinase inhibitor). We provide molecular evidences highlighting the role of EGFR, HER3, and downstream signaling pathways common to MET and HER family in resistance to MET inhibitors. Moreover, we show that an in vitro generated gastric cancer cell line resistant to MET-inhibition displays overexpression of HER family members, whose activation contributes to maintenance of resistance.ConclusionsOur findings predict that gastric cancer tumors bearing constitutive activation of HER family members are poorly responsive to MET inhibition, even if this receptor is constitutively active. Moreover, the appearance of these alterations might also be responsible for the onset of resistance in initially responsive tumors.

Small-molecule inhibitors of the human epidermal receptor family

Background: Small molecule inhibitors of human epidermal receptors (HER) have become an integral part of the armamentarium available to the medical oncologist in the treatment of solid tumor malignancies. At present, there are two small-molecule inhibitors (erlotinib and lapatinib) approved by the FDA in the USA, and a third inhibitor, gefitinib, is approved in other countries. Objective: To summarize the current standards of care for these new agents in solid tumors, and to discuss ongoing clinical trials; to review the known mechanisms of action of these inhibitors as well as to discuss both the known predictive markers for response and likely mechanisms of resistance. Methods: We reviewed key presentations and recent publications on small-molecule inhibitors targeting the HER family in solid tumors. Conclusions: Recent data have highlighted the importance of mutations and amplifications of receptors within the HER family. Amplification of HER2 often translates into responses in anti-HER2 therapy. Mutations either enhance sensitivity or confer resistance to small-molecule inhibitors. Other mechanisms of resistance are being elucidated which should lead to the ability to predict both responses and resistance to HER family inhibitors and should translate into improvements in patient care.

Epidermal growth factor receptor pathway as therapeutic development in head and neck cancers: present and future

The understanding of the epidermal growth factor pathway in terms of intracellular signaling and its role in proliferation and cell survival has impacted the therapeutic management of many solid tumor malignancies in which this pathway has been dysregulated. Once the receptor is targeted at its cellular membrane level or tyrosine kinase domain, its blockage induces downregulation of oncogenic and tumorigenesis mechanisms which were in place, and thus inhibits proliferation and induces apoptosis of the malignant cell. Nowadays, we have several monoclonal antibodies as well as small molecules which target the receptor of epidermal growth factor. Although several receptors have been described within the human epidermal receptor family, our discussion will be focused on the impact of human epidermal receptor-1 as a therapeutic option for locally advanced squamous cell carcinoma of the head and neck.

Implications of EGFR inhibition in ovarian cancer cell proliferation

Objectives Epidermal Growth Factor Receptor (EGFR) is one of the four members of the Human Epidermal Receptor (HER) family and is over-expressed in multiple malignancies. EGFR over-expression in ovarian cancer has been associated with poor prognosis. Targeted inhibition of EGFR via its tyrosine kinase domain is a successful treatment in lung cancer. Our objective was to correlate EGFR over-expression and growth inhibition, by EGF receptor inhibitors, in ovarian cancer. Materials and methods HER expression in nine epithelial ovarian cancer cell lines and one lung cancer cell line was determined by Western blot analysis. EGFR phosphorylation sites were analyzed and DNA sequencing was performed. Cell proliferation assays were performed in the presence of the tyrosine kinase inhibitor, gefitinib, and the EGFR monoclonal antibody, cetuximab. Inhibitory concentrations of 50% of these therapies were determined and compared across all cell lines. The lung cancer cell line, HCC827, was used as a control. Results Four of nine (44%) ovarian cancer cell lines and the control lung cancer cell line expressed EGFR. These same cell lines showed a common phosphorylated residue at position 992, while other residues were variably phosphorylated. All but one cell line expressed at least one HER family member. Mutational analysis of the ovarian cancer cell lines showed no mutations in EGFR exons 18–21. Cell proliferation assays using gefitinib and cetuximab showed minimal response in the ovarian cancer cell lines when compared to the control HCC827, but relative sensitivity compared to the one cell line that had no HER family expression. Conclusions Ovarian cancer cell lines show variable expression of activated EGFR. EGFR inhibition alone, in ovarian tumors that lack a tyrosine kinase mutation or over-express EGFR is unlikely to result in clinical response.

Implications of HER family inhibition in targeted therapy of ovarian cancer

13120 Background: The human epidermal receptor (HER) family couples binding of extracellular ligands to intracellular tyrosine kinase (TK) signal transduction pathways, contributing to cellular proliferation. Overexpression of HER family members has been associated with poor prognosis in ovarian cancer. There is growing evidence to support that none of the individual HER members can be considered as the stand-alone target in ovarian cancer and that cooperation between them influences therapeutic response. To evaluate this receptor cooperation in ovarian cancer our goal was to determine HER family expression and to quantify inhibition of HER1 alone compared to inhibition of HER1/HER2 combined. Methods: HER1, HER2, HER3 and HER4 expression was determined by Western blot in 9 ovarian cancer cell lines. Ovarian cancer cell proliferation was determined after inhibition of HER1 using the monoclonal antibody cetuximab, the TK inhibitor gefitinib, or combination of the two. To quantify the combined inhibition of HER1/HER2, 3 cell lines were selected with variable HER1 and HER2 expression. Cell proliferation was then determined in these 3 cell lines after treatment with cetuximab combined with the monoclonal HER2 antibody, trastuzumab. IC50 values were calculated for all treatment arms and compared. A lung cancer cell line (HCC827), with a HER1 TK mutation and sensitivity to gefitinib and cetuximab, was used as a positive control. Results: HER1 was overexpressed in 3/9 ovarian cancer cell lines, HER2 in 1/9, HER3 in 2/9, and HER4 in 4/9. Minimal to no growth inhibition was seen in the 9 cell lines after blocking HER1 with cetuximab, gefitinib, or the combination of both. In the 3 cell lines selected for HER1 and HER2 expression, there was no growth inhibition achieved despite combining cetuximab with trastuzumab. However, this treatment combination increased resistance in 1 of the 3 cell lines (HCC60), noted to overexpress HER1, 2, and 4. Conclusions: Ovarian cancer has variable HER family expression. No correlation was found between HER1 and HER2 overexpression and response to their targeted inhibition. Our findings support the concept the entire HER family plays a role in ovarian cancer growth and suggest an equilibrium shift of HER heterodimerization may play an important role in maintaining cell signaling. No significant financial relationships to disclose.

Targeting HER1/EGFR: A molecular approach to cancer therapy

The varying efficacy and toxicity of traditional cancer therapies has driven the development of novel target-based agents. Members of the HER (HumanEpidermalReceptor) family, in particular epidermal growth factor receptor (HER1/EGFR), are attractive therapeutic targets because they are overexpressed and/or dysregulated in many solid tumors. Activation of HER1/EGFR mediated through ligand binding triggers a network of signaling processes that promote tumor cell proliferation, migration, adhesion, and angiogenesis, and decrease apoptosis. Therefore, inhibiting HER1/EGFR activity could effectively block downstream signaling events and, consequently, tumorigenesis. Various approaches are being investigated to target members of the HER family, particularly HER1/EGFR and HER2. At the forefront are monoclonal antibodies and small molecules that inhibit the receptor tyrosine kinase activity. Monoclonal antibodies have been developed that act against HER1/EGFR and HER2. Monoclonal antibodies block ligand binding and prevent ligand-induced activation. Tyrosine kinase inhibitors block receptor phosphorylation, preventing downstream signal transduction. Several HER1/EGFR-targeted agents are advanced in clinical development and attention is focused on optimizing their clinical use. While this process may prove challenging, it promises to be beneficial.