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Response to Trastuzumab, Erlotinib, and Bevacizumab, Alone and In 2664 Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines David R. Emlet, Kathryn A. Brown, not increase apoptosis substantially. These studies sug- Deborah L. Kociban, Agnese A. Pollice, gest that the effects of two and three-drug combinations Charles A. Smith, Ben Brian L. Ong, of trastuzumab, erlotinib, and bevacizumab might offer and Stanley E. Shackney potential therapeutic advantages in HER2-overexpressing breast cancers, although these effects are of low Laboratory of Cancer Cell Biology and Genetics, Department of magnitude, and are likely to be transient. [Mol Cancer Human Oncology, Drexel University College of Medicine and the Ther 2007;6(10):2664–74] Allegheny-Singer Research Institute, Allegheny General Hospital, Pittsburgh, Pennsylvania Introduction Human epidermal growth factor receptor-2 (HER2), a Abstract member of the epidermal growth factor receptor (EGFR) Human epidermal growth factor receptor-2 (HER2) and family of tyrosine kinases, is overexpressed in 25% to 30% epidermal growth factor receptor (EGFR) heterodimerize to of human breast cancers (1). It has been implicated in activate mitogenic signaling pathways. We have shown cancer progression (2, 3), and has been identified as a previously, using MCF7 subcloned cell lines with graded prognostic and predictive marker for breast cancer out- levels of HER2 expression, that responsiveness to trastu- come (4). Clinically, chemotherapeutic regimens that zumab and AG1478 (an anti-EGFR agent), varied directly include trastuzumab (Herceptin), a humanized monoclonal with levels of HER2 expression. HER2 and EGFR up- antibody directed against the extracellular domain of regulate vascular endothelial growth factor (VEGF), a HER2, prolong the time to progression and increase overall growth factor that promotes angiogenesis and participates survival in patients with advanced disease whose tumors in autocrine growth-stimulatory pathways that might be amplify/overexpress HER2 (5, 6). In the adjuvant setting, in vitro active . Here, we show that trastuzumab, erlotinib, trastuzumab increases disease-free survival and overall and bevacizumab, individually and in combination, inhibit survival in patients whose tumors amplify/overexpress cell proliferation in a panel of unrelated human breast HER2 (7, 8). cancer cell lines, in proportion to their levels of HER2 EGFR is overexpressed in 15% to 35% of breast cancers, expression. The combination of all three drugs provided a and EGFR overexpression is associated with a poor greater suppression of growth than any single drug or two- prognosis (9, 10). Agents that target EGFR, including drug combination in the high HER2–expressing cell lines erlotinib (Tarceva/OSI-774), are currently approved for P ( < 0.001). Combination index analysis suggested that the management of non–small cell lung cancer, colon the effects of these drugs in combination were additive. cancer, pancreatic, and head and neck cancers (11, 12). The pretreatment net level of VEGF production in each Responses are seen in 8% to 20% of patients with non–small cell line was correlated with the level of HER2 expression cell lung cancer, with higher response rates in a subset of r P ( = 0.883, = 0.016). Trastuzumab and erlotinib each patients whose tumors contain mutations involving the reduced total net VEGF production in all cell lines. kinase domain of EGFR (13, 14). Although preclinical cell Multiparameter flow cytometry studies indicated that culture and xenograft studies suggest that EGFR-targeted erlotinib alone and the triple drug combination produced therapies may be active in breast cancer, clinical trials have a prolonged but reversible blockade of cells in G , but did 1 shown responses in <10% of patients (15). HER2 and EGFR heterodimerize with one another to drive mitogenic signaling pathways, and this interaction is Received 2/5/07; revised 7/27/07; accepted 8/30/07. likely to play a key role in cancer progression in breast Grant support: Agreement no. 41331809 with Beckman Coulter. cancer cells that overexpress HER2 and express EGFR. In The costs of publication of this article were defrayed in part by the preclinical studies, combinations of EGFR and HER2 payment of page charges. This article must therefore be hereby marked targeting agents were found to be more effective than advertisement in accordance with 18 U.S.C. Section 1734 solely to single targeted therapy agents. Combinations of EGFR- indicate this fact. targeted agents erlotinib or gefitinib (Iressa/ZD1839) with Requests for reprints: Stanley E. Shackney, Allegheny General Hospital, 10ST320 East North Avenue, Pittsburgh, PA 15212. Phone: 412-359- the HER2-targeted agents trastuzumab or pertuzumab 4306; Fax: 412-359-3238. E-mail: [email protected] (Omnitarg/2C4) have shown additive or synergistic effects Copyright C 2007 American Association for Cancer Research. on growth inhibition of cancer cells in vitro and/or in vivo doi:10.1158/1535-7163.MCT-07-0079 (16–19). Clinical results with a combination of erlotinib and Mol Cancer Ther 2007;6(10). October 2007 Downloaded from mct.aacrjournals.org on October 2, 2021. © 2007 American Association for Cancer Research. Molecular Cancer Therapeutics 2665 trastuzumab suggests that this combination is well tolera- cell lines (American Type Culture Collection) were cul- ted, and the addition of erlotinib may be able to overcome tured in the same media without geneticin. The BT474 cell resistance to trastuzumab, but the in vitro activity of the line (American Type Culture Collection) was maintained in combination has not yet been borne out in the clinic (20). DMEM containing 100 units/mL of penicillin and strepto- Breast cancer cell lines and primary breast cancers can mycin, 0.25 Ag/mL of amphotericin B, and 10% fetal bovine express vascular endothelial growth factor (VEGF), or its serum. The MDA-361 cell line (American Type Culture receptors (21–25), and increased VEGF expression in breast Collection) was maintained in Leibovitz’s L-15 Media cancers is associated with tumor progression and increased containing 100 units/mL of penicillin and streptomycin, risk of recurrence (26). Although the antiangiogenic effects 0.25 Ag/mL of amphotericin B, and 10% fetal bovine serum of agents targeted against VEGF have been emphasized in in a CO2-free incubator. cancer (27–29), tumors that express both VEGF and its Immunoblot Analysis receptors can participate in autocrine/paracrine feedback Cell lysate (50 Ag) was subjected to SDS-PAGE on 4% to loops (30–32), and the specific effects of anti-VEGF agents 20% tris/glycine gels, transferred to nitrocellulose filters, on these autocrine loops can be studied in vitro, where and blocked for 30 min in TTBS [100 mmol/L Tris (pH 7.5), angiogenesis is not at issue. 0.9% NaCl, 0.1% Tween 20] with 5% nonfat dry milk. A HER2 can regulate VEGF production in human breast monoclonal antibody against HER2 (CB11; Novacastra cancer cell lines (33, 34), and VEGF levels are correlated Labs.) was used at a 1:1,000 dilution. The secondary with HER2 expression in primary breast cancers (35, 36). antibody was goat anti-mouse horseradish peroxidase– EGFR can also up-regulate the expression of VEGF in cancer conjugated antibody (Santa Cruz Biotechnology), and was cell lines (37–39), and inhibition of EGFR activity reduces used at a 1:1,000 dilution. For the supplemental data, a VEGF production and angiogenesis in vivo (38, 40, 41). polyclonal antibody against the insulin-like growth factor- Given that HER2 and EGFR can heterodimerize to initiate IR (Santa Cruz Biotechnology) was used at a 1:200 dilution, signal transduction, and that each can regulate VEGF and the secondary antibody was goat anti-rabbit horserad- production, it would seem reasonable to compare the ish peroxidase–conjugated antibody (Santa Cruz Biotech- effects of inhibition of EGFR, HER2, and VEGF, individu- nology), used at a 1:1,000 dilution. Antibody signal was ally and in combination, in breast cancer cell lines. We have visualized using the SuperSignal West Pico Chemilumi- shown previously that responses to AG1478 (a small nescent Substrate (Pierce) exposed to Kodak BioMax XAR molecule EGFR inhibitor) alone, or in combination with film. Densitometry was done using a Personal Densitom- trastuzumab, were correlated with levels of expression of eter SI (Molecular Dynamics), and the data were analyzed HER2 in a series of MCF7 breast cancer cell line subclones using Scion Image for Windows (Scion Corporation). that expressed graded levels of HER2 (42). Growth Inhibition Assays In this study, we examine this relationship in genetically Trastuzumab and bevacizumab were provided by Gen- unrelated human breast cancer cell lines using clinically entech, erlotinib was provided by OSI Pharmaceuticals, relevant concentrations of the EGFR inhibitor erlotinib, and and the anti–insulin-like growth factor-IR antibody IMC- we have extended our studies to include the VEGF- A12 was provided by ImClone Systems. Trastuzumab, inhibiting antibody bevacizumab (Avastin). We show that bevacizumab, and IMC-A12 were stored at 4jC. Erlotinib, the triple combination of erlotinib, trastuzumab, and VEGF receptor (VEGFR) inhibitor (Calbiochem), and bevacizumab provided a greater suppression of growth etoposide (Calbiochem) were stored as 10 mmol/L stocks than any of these drugs alone or any possible two-drug in DMSO at À20jC. Cell stocks were grown to 80%
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