scholarly journals A Bispecific Inhibitor of the EGFR/ADAM17 Axis Decreases Cell Proliferation and Migration of EGFR-Dependent Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 411
Author(s):  
Abel Soto-Gamez ◽  
Deng Chen ◽  
Anke G.E. Nabuurs ◽  
Wim J Quax ◽  
Marco Demaria ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Fusion Protein ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Mutant Cell ◽  
Growth Factor Receptor ◽  
Autocrine Signaling ◽  
Inhibition Of Proliferation ◽  
Innovative Strategy ◽  
Egfr Ligands

Dysregulated epidermal growth factor receptor (EGFR) is an oncogenic driver of many human cancers, promoting aberrant cell proliferation, migration, and survival. Pharmacological targeting of EGFR is often challenged by acquired mechanisms of resistance. Ligand-dependent mechanisms in EGFR wild-type cells rely on ligand or receptor overexpression, allowing cells to outcompete inhibitors and perpetuate signaling in an autocrine manner. Importantly, EGFR ligands are synthesized as membrane-bound precursors that must be solubilized to enable receptor-ligand interactions. The A disintegrin and metalloproteinase 17 (ADAM17) is considered the main sheddase of several EGFR ligands, and a potential pharmacological target. However, its broad substrate range and ubiquitous expression complicate its therapeutic targeting. Here, we present a novel bispecific fusion protein construct consisting of the inhibitory prodomain of ADAM17 (TPD), fused to an EGFR-targeting designed ankyrin repeat protein (DARPin). TPD is a natural inhibitor of ADAM17, maintaining the protease in a zymogen-like form. Meanwhile, the high affinity anti-EGFR DARPin E01 binds to EGFR and inhibits ligand binding. The resulting fusion protein E01-GS-TPD retained binding ability to both molecular targets EGFR and ADAM17. The large difference in affinity for each target resulted in enrichment of the fusion protein in EGFR-positive cells compared to EGFR-negative cells, suggesting a possible application in autocrine signaling inhibition. Accordingly, E01-GS-TPD decreased migration and proliferation of EGFR-dependent cell lines with no significant increase in apoptotic cell death. Finally, inhibition of proliferation was observed through EGFR ligand-dependent mechanisms as growth inhibition was not observed in EGFR mutant or KRAS mutant cell lines. The use of bispecific proteins targeting the EGFR/ADAM17 axis could be an innovative strategy for the treatment of EGFR-dependent cancers.

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors

2020 ◽  
Vol 20 (18) ◽  
pp. 1628-1639
Author(s):  
Sergi Gómez-Ganau ◽  
Josefa Castillo ◽  
Andrés Cervantes ◽  
Jesus Vicente de Julián-Ortiz ◽  
Rafael Gozalbes
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Binding Affinity ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Epidermal Growth

Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.

scholarly journals Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines

2010 ◽  
Vol 207 (3) ◽  
pp. 309-317 ◽  
Author(s):  
M Arvigo ◽  
F Gatto ◽  
M Ruscica ◽  
P Ameri ◽  
E Dozio ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Membrane Receptors ◽  
Receptor Interaction ◽  
Inhibition Of Proliferation ◽  
Receptor Interactions

Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr1/sstr2, sstr2/sstr5, sstr5/dopamine (DA) type 2 receptor (D2R), and sstr2/D2R dimers. BIM-23704 (sstr1- and sstr2-preferential compound) increased the co-immunoprecipitation of sstr1/sstr2 and significantly inhibited proliferation (−30.98%). BIM-23244 (sstr2–sstr5 selective agonist) significantly increased the co-immunoprecipitation of sstr2/sstr5, and induced a −41.36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr2 and D2R and a moderate affinity for sstr5, significantly increased the sstr5/D2R and sstr2/D2R complexes and was the most powerful in inhibiting proliferation (−42.30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D2R/sstr5 and inhibiting cell proliferation (−30.54%). However, behind BIM-23A760, BIM-53097 (D2R-preferential compound) also significantly inhibited Calu-6 proliferation (−17.71%), suggesting a key role for D2R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.

Antisense to the Epstein-Barr Virus (EBV)-Encoded Latent Membrane Protein 1 (LMP-1) Suppresses LMP-1 and Bcl-2 Expression and Promotes Apoptosis in EBV-Immortalized B Cells

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1721-1727 ◽  
Author(s):  
Jamie L. Kenney ◽  
Mary E. Guinness ◽  
Tyler Curiel ◽  
Jill Lacy
Keyword(s):  
Membrane Protein ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Antitumor Agents ◽  
Apoptotic Cell ◽  
Latent Membrane Protein ◽  
Therapeutic Effects ◽  
Inhibition Of Proliferation ◽  
Barr Virus ◽  
Epstein Barr

Abstract The Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP-1) is required for viral transformation and functions to protect cells from apoptotic cell death, in part, by induction of antiapoptotic genes, including Bcl-2 and A20. We have used antisense oligodeoxynucleotides targeted to LMP-1 as a strategy to suppress LMP-1 expression and thereby inhibit its functions. We have shown that levels of LMP-1 protein in EBV-positive lymphoblastoid cell lines can be reduced by in vitro treatment with unmodified oligodeoxynucleotides targeted to the first five codons of the LMP-1 open-reading frame. Furthermore, suppression of LMP-1 was associated with molecular and phenotypic effects that included downregulation of the LMP-1–inducible antiapoptotic genes, Bcl-2 and Mcl-1, inhibition of proliferation, stimulation of apoptosis, and enhancement of sensitivity to the chemotherapeutic agent, etoposide. These effects were largely sequence-specific and observed in EBV-positive, but not EBV-negative cell lines. These studies suggest that lowering expression of LMP-1 in EBV-associated malignancy might have therapeutic effects and might synergize with other antitumor agents. © 1998 by The American Society of Hematology.

scholarly journals MiR-520b/e Regulates Proliferation and Migration by Simultaneously Targeting EGFR in Gastric Cancer

2016 ◽  
Vol 40 (6) ◽  
pp. 1303-1315 ◽  
Author(s):  
Shuang Li ◽  
Haiyang Zhang ◽  
Tao Ning ◽  
Xinyi Wang ◽  
Rui Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Over Expression ◽  
Epidermal Growth ◽  
And Migration ◽  
The Relationship ◽  
Proliferation And Migration

Background: MicroRNAs (miRNAs) have been demonstrated to play a crucial role in tumorigenesis. Previous studies have shown that miR-520b/e acts as a tumor suppressor in several tumors. Other studies indicated that epidermal growth factor receptor (EGFR) is highly expressed in many tumors, and involved in the development of tumors, such as cell proliferation, migration, angiogenesis and apoptosis. However, the correlation of miRNAs and EGFR in gastric cancer (GC) has not been adequately investigated. Our aim was to explore the relationship. Methods: The expression levels of EGFR and miR-520b/e were examined by RT-PCR and Western blot. We also investigated the relationship between EGFR and miR-520b/e in GC cell lines by relevant experiments. Results: In this study, we found that miR-520b/e inhibits the protein expression of EGFR by directly binding with the 3'-untranslated region (3'-UTR). And it was shown that the down-regulation of miR-520b/e promotes cell proliferation and migration by negative regulation of the EGFR pathway, while over-expression of miR-520b/e inhibits these properties. In addition, the biological function of EGFR in GC cell lines was validated by silencing and over-expression assays respectively. Conclusions: Taken together, our results demonstrate that miR-520b/e acts as a tumor suppressor by regulating EGFR in GC, and provide a novel marker and insight for the potential therapeutic target of GC.

Anti-CD138-IFNα Fusion Proteins Are Effective in Treating Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 939-939
Author(s):  
Esther Yoo ◽  
Alex Vasuthasawat ◽  
Danh Tran ◽  
Alan Lichtenstein ◽  
Sherie Morrison
Keyword(s):  
Multiple Myeloma ◽  
Fusion Protein ◽  
Cell Lines ◽  
Dna Content ◽  
Fusion Proteins ◽  
Conflicts Of Interest ◽  
Myeloma Cell ◽  
Inhibition Of Proliferation ◽  
Discontinue Therapy

Abstract Abstract 939 Although IFNα has shown some efficacy in the treatment of multiple myeloma (MM), this efficacy has been limited in large part because systemic toxicity makes it difficult if not impossible to reach therapeutically effective doses at the site of the tumor. The short half-life of IFN also makes it difficult to sustain high levels during treatment, and because of the side effects, the patients often discontinue therapy. To address these issues, we have genetically fused IFNα2 to a chimeric IgG1 antibody specific for the antigen CD138 expressed on the surface of MM cells, yielding anti-CD138-IFNα. We have also produced a fusion protein (anti-CD138-mutIFNα) using a mutant IFNα that binds the IFN receptor (IFNAR) more tightly. The fusion proteins continued to bind CD138 and retained IFN activity and showed anti-proliferative activity against a broad panel of myeloma cell lines (HMCL) representing MM with different characteristic. To investigate the events responsible for the inhibition of proliferation, 8226/S, ANBL-6, MM1-144, H929, OCI-My5 and U266 cells were incubated with 500 pM anti-CD138-IFNα for 72 h and their DNA content analyzed by FLOW cytometry following permeabilization and staining with PI. The different cell lines exhibited different responses. All of the cell lines except OCI-My5 underwent apoptosis. For 8226/S, OCI-My5 and U266 there was little change in DNA content following treatment. ANBL-6 showed a slight increase in the number of cells in S. However, MM1-144 and H929 showed a marked accumulation in G2 with H929 also showing accumulation of cells with sub-G0content of DNA. Therefore, there is heterogeneity in the response of different HMCL to treatment with targeted IFNα2. For many but not all of the cell lines, anti-CD138-mutIFNα was more effective than anti-CD138-IFNα in inhibiting proliferation and causing DNA fragmentation. Anti-CD138-mutIFNα was more effective than anti-CD138-IFNα in inducing senescence-associated β-galactosidase and STAT1 activation in OCI-My5 cells. Treatment with anti-CD138-IFNα or anti-CD138-mutIFNα resulted in a decrease in the amount of IRF4 present in U266, suggesting that this may be responsible for the efficacy of the fusion proteins in this cell line. Treatment of the other cell lines did not alter the level of IRF4 present, but anti-CD138-IFNα and anti-CD138-mutIFNα treatment caused a decrease in the amount of ppRB present in 8226/S, OCI-My5 and MM1-144, and to a lesser extent in H929. To determine the in vivo efficacy of fusion protein treatment, SCID mice were injected subcutaneously with OCI-My5 cells and treated intravenously on days 14, 16 and 18 with 100 μg of the indicated proteins and monitored for tumor growth (Figure 1). Mice were sacrificed when tumors exceeded 1.5 cm in diameter. Treatment with anti-CD138-IFNα provided some protection (p ≤ 0.0001 compared to PBS). However, treatment with anti-CD138-mutIFNα was even more effective (p = 0.0004 compared to anti-CD138-IFNα). Anti-CD138-mutIFNα was also found to be more effective than anti-CD138-IFNα against primary MM cells. Patients with active myeloma were biopsied while off therapy and the marrow cells isolated by a negative antibody selection to >95% purity. After 72 h incubation with 25 nM of protein, anti-CD138 was found to have little effect. In contrast treatment with anti-CD138-IFNα caused a decrease in viability with anti-CD138-mutIFNα treatment leading to an even greater decrease in cell viability. Following 72 h of treatment, 25 nM of anti-CD138-mutIFNα was found to have more potent cytoreductive effects than 100 nM of anti-CD138-IFNα. Disclosures: No relevant conflicts of interest to declare.

Evaluation of antiproliferative and apoptotic effects of the rational combination of the MEK1/2 inhibitor selumetinib (AZD6244) and inhibitors of the hedgehog pathway in colorectal cancer (CRC) cell lines.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 422-422
Author(s):  
A. Spreafico ◽  
J. J. Tentler ◽  
A. Tan ◽  
T. M. Pitts ◽  
M. I. Kachaeva ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mapk Pathway ◽  
Mutant Cell ◽  
Gene Array ◽  
Combination Strategy ◽  
Cell Viability Assay ◽  
Inhibition Of Proliferation ◽  
Antiproliferative Effects ◽  
Rational Combination

422 Background: The MAPK pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. Hyperactivation of this pathway due to mutations in KRAS have been reported in up to 50% of CRC cases. Clinical trials have shown that KRAS patients do not benefit from therapies targeting EGFR, highlighting the need for new therapeutic options. Utilizing differential gene array analyses, we have identified the hedgehog (HH) signaling pathway as a potential mediator of resistance to AZD6244. Based on these results, we tested the rational combination of selumetinib and the HH inhibitor, cyclopamine against human CRC cell lines. Methods: CRC cell lines were exposed to varying concentrations of selumetinib and cyclopamine. For AZD6244, cell lines with IC50≤ 0.1 μM were considered extremely sensitive (ES) and those with IC50≥ 1μM were deemed extremely resistant (ER). Four KRAS mutant cell lines (2ES, 2ER) were selected for combination studies. The antiproliferative effects were assessed using the sulforhodamine B (SRB) cell viability assay, and potential synergy was evaluated using the Chou and Talalay method. Apoptosis was analyzed using bioluminescent caspase 3/7 detection. Results: In all four cell lines tested, synergistic antiproliferative effects of selumetinib and cyclopamine were observed, including resistant lines to selumetinib. We observed significant induction of apoptosis when cell lines were exposed to the combination treatment, independent of their responsiveness to selumetinib in the SRB assay. Conclusions: Treatment of KRAS mutant CRC cell lines with selumetinib and cyclopamine resulted in synergistic inhibition of proliferation, regardless of sensitivity to selumetinib. Interestingly, a significant increase in apoptosis was observed in response to the combination, which may explain the synergy observed by the combination index (CI). In vivo analyses of this combination in cell lines and human CRC explants are ongoing to further validate these results. These preclinical data may suggest a rational combination strategy for patients with KRAS mutant CRC. No significant financial relationships to disclose.

Identification of head and neck cancers (SCCHN) that may respond to dual inhibition of EGFR and HER3 signaling.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5575-5575
Author(s):  
David S. Shames ◽  
Howard Stern ◽  
Kim Walter ◽  
Brittany Jiang ◽  
Ling Fu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Bimodal Distribution ◽  
Autocrine Signaling ◽  
Oncogenic Signaling ◽  
Epithelial Cancers ◽  
Formalin Fixed Paraffin Embedded ◽  
Dual Action ◽  
High Level

5575 Background: Oncogenic signaling through the epidermal growth factor receptor family is one of the most frequent alterations found in human epithelial cancers. These receptor tyrosine kinases mediate their effects via high-level co-expression and homo- and heterodimerization events that drive tumor growth, metastasis, and survival. Extensive preclinical studies suggested that some cell lines depend on oncogenic autocrine signaling through HER3 (Wilson et al.). This phenotype was particularly prominent in cell lines derived from SCCHN and was strongly correlated with high HRG expression. Interestingly, two patients with SCCHN tumors that expressed high levels of HRG in our phase Ia trial (abstract #95245) of MEHD7954A, a dual-action human IgG1 antibody that blocks ligand binding to EGFR and HER3 (Schaefer et al.) had partial responses. To further explore the hypothesis that high-level HRG expression defines a sub-population of SCCHN that may be sensitive to agents targeting HER3, and to identify other potential target indications for the development of MEHD7954A, we evaluated the expression of HRG in large cohorts of multiple solid tumor indications. Methods: HER3 and HRG expression was analyzed by qRT-PCR in 648 formalin-fixed paraffin embedded primary tumor samples from patients with NSCLC, SCCHN, melanoma, CRC and triple-negative breast cancer. Results: SCCHN-derived tumor samples had the highest levels of HRG expression, exhibiting a bimodal distribution in SCCHN – a pattern that is clearly distinct when compared to other tumor types. These data suggest that high HRG levels and potentially HER3-dependent autocrine signaling occur more frequently in SCCHN than in other tumors. Further we investigated whether overexpression of HRG in SCCHN correlated with stage and disease outcome. Updated results from these extended studies will be presented. Conclusions: SCCHN tumors exhibit bimodal expression of HRG, suggesting that HRG expression levels may be useful in identifying a subset of patients most likely to benefit from inhibition of HER3 activity. Antitumor activity in such patients has been observed in a phase I study of MEHD7954A (abstract #95245).

Effect of sequential docetaxel followed by mTOR inhibitor temsirolimus on suppression of PI3K overactivation resistance mechanism.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 88-88 ◽  
Author(s):  
Chao Hui Huang ◽  
Peter J. Van Veldhuizen ◽  
Ayten Gadashova ◽  
Stephen K. Williamson ◽  
Faris Farassati
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Lines ◽  
Cancer Cell ◽  
Mtor Inhibitor ◽  
Growth Factor Receptor ◽  
Lung Cancer Cell ◽  
Time Points ◽  
Opposite Sequence

88 Background: Mammalian target of rapamycin (mTOR) is a downstream regulatory protein of the PI3K/Akt signal transduction pathway. This is a common pathway for a several cell surface receptors including IGFR (Insulin-like Growth Factor Receptor) and EGFR (Epidermal Growth Factor Receptor). The activation of these receptors through PI3K/Akt pathway is essential in cell proliferation, angiogenesis, and anti-apoptosis process. The upregulation of PI3K could be a mechanism of resistance of mTOR inhibitors. Docetaxel (D) is commonly used in the treatment of lung cancer. We demonstrated previously that the sequence of D followed by mTOR inhibitor temsirolimus (T) in lung cancer cell lines (LCCL) had synergistic effect in suppressing cell proliferation compared with T→D. The exact mechanism of this effect is unknown. We studied the expression of mTOR and PI3K in these cell lines treated in different time points to investigate the activity of this pathway when using these sequences of drug treatment. Methods: Adenocarcinoma LCCL H2122 and H1437 were plated and exposed to temsirolimus 1000nM and docetaxel 100nM. The cell viability was measured by optical density (OD) at 24, 48, and 72h. We tested effect of drugs D and T alone as well as the sequence of D treated for 24h followed by addition of T and the reverse in both LCCL. We then prepared cell lysate at 24h, 48h, and 72h time points and studied the expression of phospho mTOR (pmTOR) and PI3K by western blot using antibody obtained from cell signaling. Results: The use of T alone increased the expression of PI3K in both H2122 and H1437 cell lines at 48h time point. The use of D had a variable response: absent in H1437 and present in H2122 at 48 H. The sequence of D→T suppressed the expression of pmTOR and PI3K at 48 and 72 h compared with the opposite sequence of T→D. Conclusions: The combination of D → T is synergistic in suppression of pmTOR and inhibited the overactivation of upstream PI3K in both LCCL compared with opposite sequence. Therefore, the sequential treatment of D followed by T is able to overcome the PI3K overactivation mechanism of resistance in lung cancer cell line when treated with T. This would have implications in the use of these agents in treatment of lung cancer.

Epidermal growth factor receptor (EGFR) inhibition in triple-negative breast cancer (BrCa)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14071-14071 ◽  
Author(s):  
B. Corkery ◽  
N. O’Donovan ◽  
M. Clynes ◽  
J. Crown
Keyword(s):  
Cell Lines ◽  
Hormone Receptors ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Growth Factor Receptor ◽  
Significant Inhibition ◽  
Inhibition Of Proliferation ◽  
Egfr Inhibition ◽  
Negative Cell ◽  
Egfr Expression

14071 Background: Triple-negative BrCa lacks expression of hormone receptors and HER-2 but does express EGFR. It is associated with early relapse and poor survival. There is no targeted therapy for triple-negative BrCa. We are studying the potential role of EGFR inhibition. Methods: EGFR expression was examined in triple-negative BrCa cell lines, (BT20, HCC1937, and MDA-MB-231) by western blot. IC50 assays were determined for three EGFR inhibitors, gefitinib (G) and erlotinib (T), which are small-molecule tyrosine kinase inhibitors, and cetuximab (E) which is a monoclonal antibody against EGFR, and chemotherapy (CRx) drugs docetaxel (D) and carboplatin (P)), using the acid phosphatase assay. The controls were HER2+ BrCa cell lines, BT474 and SKBR3 which express low levels of EGFR. Results: The three triple-negative cell lines over-express EGFR. IC50 values for G and T were significantly higher in the triple-negative than in the HER2+ cell lines. E did not cause significant inhibition in any cell line (max inhibition 20% at 100 μg/ml E). IC50 values for G were lower than for T in the triple-negative cell lines (IC50s for HCC1937: G - 8.4 ± 1.5 μM; T - 26.2 ± 9.3 μM). Combined EGFR inhibition with CRx was tested in HCC1937 cells. G combined with P or with D for 5 days showed an additive effect on inhibition of proliferation ( Table 1 ). Alternate scheduling of the drugs did not significantly influence response. Conclusions: Our results suggest that triple-negative BrCa cells over-express EGFR but are not as sensitive to EGFR inhibition as HER2+ BrCa cells. However, EGFR inhibition may enhance response to CRx in triple-negative BrCa. [Table: see text] No significant financial relationships to disclose.

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