This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mendelsohn, J. Search for Related Content PubMed PubMed Citation Articles by Mendelsohn, J. Social Bookmarking                            What's this?

Targeting the Epidermal Growth Factor Receptor for Cancer Therapy

From the University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to John Mendelsohn, MD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 91, Houston, TX 77030-4009; email: jmendelsohn{at}mdanderson.org

	INTRODUCTION

TOP INTRODUCTION RATIONALE MECHANISMS OF ACTION RESULTS OF CLINICAL TRIALS FUTURE DIRECTIONS REFERENCES

 
IN 1981 AT THE University of California, Dr Gordon Sato and I hypothesized that a monoclonal antibody that binds to epidermal growth factor (EGF) receptors and that can block the binding of either EGF or transforming growth factor-alpha (TGF-) might prevent cell proliferation by inhibiting the signal transduction pathways that depend on activation of the EGF receptor.^1-3

	RATIONALE

TOP INTRODUCTION RATIONALE MECHANISMS OF ACTION RESULTS OF CLINICAL TRIALS FUTURE DIRECTIONS REFERENCES

 
The rationale behind this is worth reviewing, because there was evidence from a variety of sources that led us to this hypothesis. EGF had been identified as early as 1962, and its receptor was purified and characterized by Stanley Cohen in 1980.^4,5 He received the Nobel Prize in Physiology and Medicine for this body of work a few years later. Also, in 1980, Dr Gordon Sato was completing a decade of research, demonstrating that serum is required for cells to grow in culture because it provides growth factors.⁶ In 1980, in a seminal paper, Sporn and Todaro⁷ put forth the autocrine hypothesis that cancer cells can bypass restrictions on their growth by producing their own growth factors and autostimulating receptors on the cell’s surface. In addition, there was the knowledge that circulating antibodies can block the function of receptors in people and produce disease (experiments of nature): in myasthenia gravis, circulating antibodies inhibit the acetylcholine receptor; there are forms of hyper- and hypothyroidism in which antibodies against thyroid-stimulating hormone inhibit or stimulate thyroid function; and there are rare forms of diabetes in which circulating antibodies against the insulin receptor can mimic diabetes.

In 1981, evidence was being reported that EGF receptors are overexpressed on cancer cells; subsequently, we have learned that one third of all epithelial cancers express high levels of EGF receptors, and in many cases, this correlates with a poor prognosis.⁸ Also in the early 1980s it was learned that the EGF receptor and src, one of the first well-characterized oncogenes, share the novel property of being a protein tyrosine kinase.^9-11 Subsequently, the EGF receptor was identified as a cellular oncogene with homology to the v-erb-b viral oncogene, and experiments with gene transfer and with transgenic mice showed that overexpression of the EGF receptor can be a transforming event.^12-15 These data suggested that if we could block the binding of EGF or TGF- to the EGF receptor, we could inhibit the activity of a receptor that was relevant to cancer, targeting what turned out to be a cellular oncogene.

In 1983 and 1984, my colleagues and I published a series of papers demonstrating that blockade of the EGF receptor with murine monoclonal antibody 225 could inhibit the proliferation of cells, both in culture and in human tumor xenografts.^1,2,16 We also demonstrated that blocking this receptor inhibited its tyrosine kinase activity.³ This was the first example of an inhibitor of a tyrosine kinase that could produce inhibition of cell growth in culture and inhibition of tumor growth in vivo, and as far as I know, this was the first example of a targeted therapy against an oncogene product.

Subsequently, other inhibitory antibodies have been produced against the EGF receptor, and a number of low-molecular-weight tyrosine kinase inhibitors have been synthesized which act intracellularly on the receptor by blocking the adenosine triphosphate (ATP) binding site. All of these have the same objective—to stop the signal transduction that is initiated by activating the EGF receptor.

Also soon after our report, Drs Jeffrey Drebin, Mark Greene, and Robert Weinberg reported the first monoclonal antibody against HER-2 with antiproliferative activity, and this was soon followed by Genentech’s production of a monoclonal antibody against HER-2.^17,18 Dr Dennis Slamon reported overexpression of HER2 in 25% to 30% of patients with breast cancer and led successful clinical trials with the humanized version of this antibody, known as trastuzumab (Herceptin; Genentech, South San Francisco, CA).^19,20

C225, the human:murine chimeric antibody derived from murine monoclonal antibody 225, is an immunoglobulin G (IgG) molecule that can bind complement.²¹ C225 binds with high affinity to the EGF receptor, higher than the natural ligands. It competitively inhibits binding of the growth factor to its receptor and inhibits activation of the receptor tyrosine kinase.

A number of other monoclonal antibodies have been produced against the EGF receptor. The first, R3, from Dr Michael Waterfield’s laboratory, does not block ligand binding and was explored clinically as a carrier targeting radioactive molecules to EGF receptor–bearing cells.²² ABX-EGF, EMD 72000, and h-R3 are monoclonal antibodies that act in a manner similar to C225.^23-25 In addition, a number of bispecific antibodies are in clinical trials, where one arm of the antibody binds to the EGF receptor and the other arm binds either to lymphocytes or to the IgG receptor on monocytes and macrophages.^26-28 The goal is to attract these immune and inflammatory cells to tumor cells bearing high levels of EGF receptors.

A large number of low-molecular-weight, soluble molecules that act on the receptor intracellularly have been developed and are in clinical trials.^29-38 These can be organized into four categories: EGF receptor specific and reversible, receptor specific and irreversible, and agents that bind to more than one receptor in the EGF receptor family, either reversible or irreversible (Table 1) (Mendelsohn and Baselga, manuscript submitted). Among these, ZD1839 and OSI-774 are in phase III trials and are submitted for review by the United States Food and Drug Administration, as is C225. In this review, I will focus on examples of research findings with these three agents.

	MECHANISMS OF ACTION

TOP INTRODUCTION RATIONALE MECHANISMS OF ACTION RESULTS OF CLINICAL TRIALS FUTURE DIRECTIONS REFERENCES

Two other characteristics that I will add to the scorecard are shown in Table 2. EGF receptor inhibition can inhibit repair or recovery after chemotherapy or radiation. And, in the case of the monoclonal antibodies but not the other agents, there is the possibility of an immunologic attack on the target cell resulting from antibody binding.

I will present data demonstrating the effects of EGF receptor inhibition on these characteristics of human cancer. Figure 1 from Dr Jose Baselga demonstrates the inhibition of signaling pathways when EGF receptors are blocked with ZD1839.⁴⁰ The cells in Fig 1 are the A431 squamous carcinoma cell line, which expresses high levels of EGF receptors and produces large amounts of TGF-. There is prominent staining of tyrosine-phosphorylated EGF receptors in the control cultures, and tyrosine phosphorylation is markedly reduced in cultures incubated with the inhibitor. Two key downstream effects of EGF receptor activation were also examined. Phosphorylation of MAP kinase was inhibited, and AKT, the downstream pathway that is important for regulating apoptosis and other functions, was blocked from phosphorylation in cultures incubated with the inhibitor of EGF receptor tyrosine kinase. Similar results were reported in our studies with C225 and have been observed with other EGF receptor inhibitors.

View larger version (49K): [in this window] [in a new window]   Fig 1. Mechanisms of receptor activation. EGF receptors and members of the same receptor family (HER-2, -3, -4) became activated by dimerization. After receptor dimerization and activation of intrinsic protein tyrosine kinase activity, tyrosine autophosphorylation occurs. These events result in recruitment and phosphorylation of several intracellular substrates, leading to mitogenic signaling and other cellular activities. Data adapted.40

Drs Wu and Zhen Fan in my laboratory first determined the molecular mechanism accounting for inhibition of cell proliferation.⁴³ Figure 2 depicts results of an experiment with DiFi cells grown in culture for 24 hours either in the absence or in the presence of monoclonal antibody 225.⁴⁴ Blockade of EGF receptor activity resulted in a marked increase in the amount of p27^KIP1, an inhibitor of cyclin-dependent kinases. An assay of cyclin-dependent kinase–2 activity, measured by the ability of immunoprecipitates from cell lysates to phosphorylate histone as a substrate, showed marked inhibition after cells were cultured in the presence of C225. The lower panel in Fig 2 displays the levels of phosphorylated RB protein. In the actively proliferating control cells, most of the RB protein is in the hyperphosphorylated form, which releases transcription factors. In cells incubated with antibody 225 for 24 hours, most of the RB is in the hypophosphorylated state, which binds transcription factors. This same mechanism involving p27^KIP1 has subsequently been shown to explain the growth inhibitory activity of Herceptin, as well as soluble EGF receptor inhibitors. It appears that p27^KIP1 is a common pathway for inhibiting cell growth when the tyrosine kinase activity of receptors in the EGF receptor family is blocked.⁴⁴

View larger version (32K): [in this window] [in a new window]   Fig 2. Effects of monoclonal antibody (mAb) 225 on p27Kip1 and its association with cyclin-dependent kinase–2 (CDK2). (Top panels) Amounts of p27Kip1 protein in control cultures of DiFi colon adenocarcinoma cells and in mAb-treated cultures were determined by sodium dodecyl sulfate (SDS)–gel electrophoresis of cell lysates followed by Western blotting with a rabbit anti-p27Kip1 antibody. (Second and third panels) DiFi cells were cultured in the absence or presence of mAb 225 and cell lysates were immunoprecipitated with antibody against cycle E or CDK2 and assayed for the capacity of CDK2 to phosphorylate histone H1 as a substrate. (Bottom panel) DiFi cells were cultured in the absence or presence of mAb 225, and cell lysates were subjected to SDS-gel electrophoresis followed by Western blotting with an antibody against Rb protein. Reprinted with permission.43

EGF receptors also appear to regulate apoptosis in cancer cells. Dr Rakesh Kumar, my collaborator for many years, performed an experiment with the DiFi colon carcinoma cell line, which has very low levels of both the apoptosis inhibitor BCl-2 and the proapoptotic molecule Bax.⁴⁷ When these cells were incubated with C225 over a period of 48 hours, there was a steady increase in the amount of Bax, unopposed by BCl-2. The DiFi cells underwent apoptosis after 48 hours in culture. Most cells in growing culture are inhibited rather than killed when their EGF receptors are blocked.

An experiment in Dr Zhen Fan’s laboratory examined caspases-8 and -9 in cultured DiFi cells.⁴⁸ When the cells were exposed to ultraviolet radiation, caspases-8 and -9 were activated and the cells underwent apoptosis. When the cell cultures were exposed to monoclonal antibody C225, there was a rise in caspase-8 and in caspase-9 with comparable kinetics and levels, accompanied by apoptosis. In experiments with other cell lines, EGF receptor blockade produced a reduction in the levels of BCl-2. In a variety of experiments, proapoptotic molecules were potentiated and antiapoptotic molecules were depressed as a result of blocking the EGF receptor–signaling pathway.

Turning to angiogenesis, experiments by Drs Robert Kerbel, Josh Fidler, Colin Dinney, and Robert Radinsky demonstrated profound effects of EGF receptor blockade.^49-51 For example, Dr Dinney studied a bladder transitional cell carcinoma line. These cells were shown to produce large amounts of vascular endothelial growth factor (VEGF) in culture, and in the presence of C225, VEGF production was almost completely inhibited. In parallel, there was reduced production of interleukin-8 and of basic fibroblast growth factor. Thus, production of three pro-angiogenic molecules can be reduced or eliminated by blocking the EGF receptor. In vivo studies by Dr Dinney with orthotopic xenografts in nude mice demonstrated that treatment with C225 reduced tumor vasculature and caused reduction in the tumor cell content of VEGF, interleukin-8, and basic fibroblast growth factor.⁵⁰

In a similar study by Dr Radinsky, mice bearing pancreatic xenografts were treated with either gemcitabine, the most active drug against pancreatic cancer, or C225 or both agents (Fig 3).⁵¹ The Texas red stain for CD31 shows vascular endothelial cells lining the blood vessels of the control xenografts. The green terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling stain for terminal transferase shows few dead cells in the controls. In the gemcitabine-treated animals, apoptosis of tumor cells is increased. In the animals treated with C225 antibody, some apoptotic (green) tumor cells are seen, and some of the vascular endothelial cells are stained red for CD31 antigen. The yellow staining of vascular endothelial cells, produced by the green color superimposed on red, indicates that they are undergoing apoptosis. There are two potential explanations for this observation. In this study, the tumor cells in the treated animals produced fewer angiogenic factors, which may actually be survival factors for the new vascular endothelial cells.⁵² Alternatively, Dr Fidler has shown recently that when angiogenesis occurs in the presence of cancer cells secreting large amounts of TGF- or EGF, the vascular endothelial cells express EGF receptors which are not normally found on these cells. EGF receptor blockade might be selective by targeting these vascular endothelial cells in the tumor tissue, resulting in cell death.⁵²

View larger version (46K): [in this window] [in a new window]   Fig 3. Immunofluorescence double-staining for CD31 (endothelial cells) and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL; apoptotic cells) in L3.6pl human pancreatic tumors after 18 days of therapy. Frozen tissue sections were fixed, treated with a rat anti-CD31 antibody, and then incubated with goat anti-rat IgG conjugated to Texas Red. After the sections were washed, TUNEL was performed using a commercial kit with modifications. Immunofluorescence microscopy was performed using x400. Endothelial cells were identified by red fluorescence. DNA fragmentation was detected by localized green florescence, and by yellow fluorescence within apoptotic cells. Reprinted with permission.51

In 1987, Dr Michael Sela’s laboratory reported that another antibody against the EGF receptor (one that is not in clinical trials), when combined with cisplatinum, had additive or synergistic antitumor effects in a nude mouse model.⁵³ This report stimulated the hypothesis that receptor blockade may augment the antitumor effects of conventional chemotherapy or radiotherapy. A great deal of data have accumulated, supporting this concept.

One of the first studies in our laboratory was done by Dr Fan with well-established A431 squamous carcinoma xenografts (Fig 4). ⁵⁴ When these tumors were treated either with 225 antibody alone, or with cisplatin alone at the maximum-tolerated doses, there were no responses, but when combined therapy was given, tumors were eradicated. Comparable results were obtained by Dr Jose Baselga, combining C225 with doxorubicin against A431 xenografts and with paclitaxel against MDA468 breast adenocarcinoma xenografts.^55,56

View larger version (15K): [in this window] [in a new window]   Fig 4. Eradication of A431 cell xenografts by combination treatment with 225 monoclonal antibody (MAb) and cis-DDP (cisplatin). A431 cells (107) were implanted subcutaneously into nude mice and allowed to grow for 8 days. (A) Mice were given intraperitoneal injections of either phosphate-buffered saline (•), two injections of cis-DDP (150 µg/25 g mouse weight) on days 8 and 18 (), or 225 MAb, 1 mg/mouse, twice a week for 4 weeks, with () or without () two injections of cis-DDP (150 µg/25 g mouse weight) on days 8 and 18. Arrows indicate timing of drug and antibody treatment. Data are expressed as the mean tumor size ± SE (seven mice per group). (B) Mice were observed for 6 months for survival. Reprinted with permission.54

View larger version (26K): [in this window] [in a new window]   Fig 5. Effect of ZD1839 alone and in combination with paclitaxel (PTXL) against the LX-1 tumor (three experiments [average] with three to four mice per group, with SE < 13%). Animals were treated with ZD1839 (qd x 5) x 2 and PTXL (every 3-4 days x 4). Reprinted with permission.57

These examples from numerous preclinical studies with anti–EGF receptor agents demonstrate the potential efficacy of these therapies in cancer treatment, and clearly explain the rationale justifying their use in combination with chemotherapy. The results of clinical trials with thousands of patients support the promise of anti–EGF receptor therapy, and as noted, trials for accelerated approval with three of these agents have been submitted to the Food and Drug Administration. Results from some of the trials with C225, ZD1839, and OSI-774 will be summarized.

	RESULTS OF CLINICAL TRIALS

TOP INTRODUCTION RATIONALE MECHANISMS OF ACTION RESULTS OF CLINICAL TRIALS FUTURE DIRECTIONS REFERENCES

 
Following up on the preclinical observations, a critical clinical trial was carried out by Dr Dong Shin in patients with advanced head and neck cancer who had tumor progression on combination chemotherapy.⁶⁰ Of nine assessable patients, six had a partial or complete response to treatment with C225 plus cisplatin. Remarkably, three of these six patients had previously received cisplatin and had experienced resistance while on this chemotherapy. When these patients were subsequently treated with a combination of cisplatin and C225, there were two complete responses and one partial response—an outcome that is very unusual after cisplatin failure. Figure 6 shows disappearance of subcutaneous metastases in one of these patients, and histologic examination of a biopsy demonstrated absence of free EGF receptors due to either receptor downregulation or receptor precoating with antibody C225. Receptor tyrosine kinase activity in tumor biopsy specimens was shown to be inhibited in these patients.

View larger version (72K): [in this window] [in a new window]   Fig 6. Tumor EGF receptor (EGFr) saturation with C225 detected by immunohistochemistry studies on tumor specimens from a patient with responding disease. (Top panels) Multiple dermal metastases in the anterior neck and upper chest (left) were analyzed for EGFr expression (center) by immunohistochemistry (x200). Hematoxylin and eosin staining (H x200) of the adjacent section (right). (Bottom panels) After one course of C225 with cisplatin, multiple dermal metastases have completely regressed (left), and EGFr expression was downregulated (center). H staining of the adjacent tissue section (right). Of note, 95% EGFr saturation with C225 in tumor tissue was observed by image analysis after therapy. Reprinted with permission.60

Many clinical trials have explored the use of EGF receptor inhibitors for the treatment of non–small-cell lung cancer. The most extensively studied agent is ZD1839. In a phase II trial carried out in Europe and Japan, the partial response rate was 19%.⁶⁵ Interestingly, European responses were 11% whereas Japanese response rates were 27.5% for reasons that may relate to severity and extent of disease, differences in prior treatment, differences in male:female ratios and performance status, or differences in the number of adenocarcinomas. A recent phase II ZD1839 trial in the United States, reported by Dr Mark Kris, showed a partial response rate of 10%.⁶⁶ Results are awaited from a large and fully enrolled randomized phase III trial of first-line chemotherapy (two alternative regimens) with ZD1839 or with placebo.

A phase II trial in previously treated non–small-cell lung cancer has been carried out with OSI-774. The complete response rate was 2% and the partial response rate was 11%.³⁵ In a phase II trial reported by Dr Edward Kim, treatment with C225 plus docetaxel resulted in a 26.7% partial response rate.⁶⁷

C225 treatment has been explored in carcinoma of the colon. In a preclinical study carried out by Dr Dan Hicklin, HT29 colon carcinoma xenografts were treated with irinotecan.⁶⁸ The tumors that failed to respond to irinotecan were then randomized for treatment with C225 alone, irinotecan alone, or a combination of C225 plus irinotecan. While 225 partially reduced the growth of the xenografts and irinotecan also partially reduced growth, the combination completely arrested tumor growth. The combination therapy also markedly reduced the proliferation index of cancer cells and enhanced apoptosis.

A phase II clinical trial that followed this model was reported by Dr Leonard Saltz.⁶⁹ In this case, patients with advanced colorectal cancer expressing EGF receptors were placed on irinotecan and followed. When progression on irinotecan was documented, the drug was continued and C225 antibody therapy was added. Of the 120 patients who had progressed on irinotecan, 22.5% achieved a partial response when C225 was added to the irinotecan. In a follow-up phase II trial conducted by Dr Saltz, patients with colorectal carcinoma whose irinotecan treatment failed were treated with single-agent monoclonal antibody C225, and an 11% partial response rate to C225 therapy was observed (L. Saltz, personal communication, April 2002). A randomized phase III trial treating colorectal carcinoma with irinotecan plus or minus C225 has been fully enrolled, and results are awaited.

Some interesting data came out of the phase II combination therapy trial.⁶⁹ One can ask the question of whether high levels of EGF receptor expression are required for response to antireceptor therapy. The response rate in patients who had 1+, 2+, or 3+ levels of receptor expression in biopsy tissue from their tumors was around 22%, regardless of the level of EGF receptor expression. This is in contrast to the experience with Herceptin, the inhibitory monoclonal antibody that blocks HER-2. For Herceptin, a high, 3+ level of receptor expression is required for optimal response to second-line therapy, and in first-line therapy, nearly all of the responders were patients with breast cancer expressing high levels of HER-2. It is likely that the relevant criterion predicting a response to an EGF receptor inhibitor is the degree of dependence on the autocrine pathway, for which surrogate markers might be the level of receptor expression plus the level of production or EGF or TGF-.

Another interesting observation in Dr Saltz’s study relates to the major side effect of treatment with C225, an acneiform skin rash. Of the 27 responders in his study, 26 had a skin rash; only one responder did not have a skin rash. Thus, in this clinical trial, a skin rash appeared to identify patients whose cancers were more likely to respond to EGF receptor inhibition, although the majority of those with a rash did not respond.

There are reports of laboratory studies suggesting that the combination of an EGF receptor inhibitor plus a biologic agent may have synergistic antitumor activity. Both Dr Carlos Arteaga and Dr Mark Moasser have shown that ZD1839 can inhibit proliferation of breast adenocarcinoma cell lines bearing EGF receptors as well as high levels of HER-2.^70,71 Combination therapy with ZD1839 plus Herceptin produced enhanced antitumor activity, resulting in apoptosis of cultured cells. This is very interesting but not surprising, since the HER-2 receptor forms a heterodimer with the EGF receptor (or with HER-3) when it is activated.

Another suggestion for combination therapy comes from Dr Christopher Torrance using mice that had been genetically altered by expression of an abnormal APC (adenomatous polyposis coli) gene.⁷² These mice develop pathology comparable to the human disease. In the untreated situation, there were 32 polyps per colon. In mice treated with EKB-785, a low-molecular-weight inhibitor of the EGF receptor tyrosine kinase, there was a 52% reduction in polyps. With sulindac, a cyclo-oxygenase 2 (COX-2) inhibitor, there was a 31% reduction in polyps. When EGF receptor inhibition was combined with COX inhibition, there was a 97% reduction in polyps (one polyp). There are ongoing clinical trials with COX-2 inhibitors in colon cancer, and there is a strong rationale for future trials combining an EGF inhibitor with a COX-2 inhibitor.

EGF receptor blockade combined with radiation therapy has also been explored in preclinical experiments and in clinical trials. Dr Paul Harari has investigated head and neck squamous carcinoma cell lines growing in culture and in xenografts. The combination of radiation plus C225 or ZD1839 resulted in enhanced antitumor activity against xenografts.^42,73 Similar results were reported by Dr Luka Milas in studies of radiation plus C225 treatment of A431 squamous carcinoma xenografts.⁷⁴

The first clinical trial with radiotherapy plus C225 was reported recently.⁷⁵ In this phase I/II study, radiation was combined with C225 in patients with advanced head and neck cancer. In these patients, the expected complete plus partial response rate to radiation therapy alone is 60% to 70%. In the clinical trial combining radiation with C225 treatment, 12 out of the 14 patients had complete responses, and one other patient converted to a complete response. At 19 months, 60% of these patients were still in complete remission. Accrual to a multi-institution, phase III trial, randomizing radiation with and without C225, has been completed and the results are awaited.

Table 3 summarizes the main adverse events and side effects from 21 trials with C225 involving 813 patients (provided by ImClone Systems, Inc, New York, NY). Seventy-seven percent of patients experienced an acneiform rash, and 16% had a severe rash (grade 3 or 4). Less than 2% had an anaphylactoid or anaphylactic reaction, almost invariably after the first exposure to the antibody. Presumably this represents an inherent allergy to the mouse component of the protein in the antibody. Responses to administration of diphenhydramine hydrochloride, steroids, or in some cases epinephrine were prompt and complete. The side effect profiles for the oral anti–EGF receptor agents at doses determined to be the maximum-tolerated doses are similar to that shown in Table 3, with the exception that diarrhea is a more prominent side effect, presumably due to greater penetration of drug through the natural barrier in the gastrointestinal mucosa.⁶⁵

	FUTURE DIRECTIONS

TOP INTRODUCTION RATIONALE MECHANISMS OF ACTION RESULTS OF CLINICAL TRIALS FUTURE DIRECTIONS REFERENCES

 
EGF receptor–targeted therapies present opportunities and challenges for the future. We need to further explore schedules and combinations that optimize therapeutic results. Most studies to date have been on advanced disease, and it will be important—as with any new therapy—to see the results with early stages of disease.

The response rates in current studies with each of the anti–EGF receptor agents represent only a fraction of the patients treated. It would be preferable to identify markers that enable oncologists to preselect tumors that are likely to be responsive to EGF receptor inhibition. This is a challenge with all forms of cancer therapy that we use today. We need to obtain pretreatment tumor biopsy specimens to assess EGF receptor expression and phosphorylation, the levels of TGF- and EGF, and the levels of active (phosphorylated) MAP kinase and active AKT, as potential markers that might predict the activity of EGF-mediated autocrine signaling in a particular tumor. Likewise, we should seek markers to enable us to determine, early in the course of therapy, which patients are responding to anti–EGF receptor treatment. We need to study biopsy specimens of tumors a few days after initiation of treatment, and measure changes in the levels of EGF receptor phosphorylation, HER-2 phosphorylation, and phosphorylation of MAP kinase and AKT. With these types of approaches, some of which are planned or are ongoing in current trials, we hope to learn how to use cancer treatments involving inhibition of EGF receptors more intelligently.

The only way to determine the comparative merits of the variety of new agents that block the EGF receptor activity is to perform clinical trials. The extracellular approach to EGF receptor blockade with a monoclonal antibody and the intracellular approach with an ATP binding site blocker have a great deal in common, and each approach has potential merits. The agents in the two classes differ in absolute specificity for the EGF receptor, the potential for dose-dependent toxicity, and the types of adverse events that have been reported. Also, the route of administration of antibodies is intravenous, whereas most of the agents that block the ATP binding site are administered orally.

In 1997, Dr Monique Bos in my laboratory published a study showing that combined treatment with C225 antibody plus PD153035, an early soluble inhibitor of the EGF receptor, produced greater antitumor activity than either agent alone against a number of cultured cells lines.⁷⁷ This suggests that clinical trials with a combination of anti–EGF receptor agents that involve different mechanisms of action should be performed in the future.

In conclusion, we and others have shown that inhibitors of EGF receptor tyrosine kinase activation are active anticancer agents in the clinic. This approach to cancer therapy initiated the concepts of inhibiting tyrosine kinases and oncogene products, concepts that are rapidly being expanded to include numerous targets. There is strong evidence that combination treatment with an EGF receptor inhibitor plus either chemotherapy or radiation therapy produces enhanced antitumor responses. I believe this will be the major way that agents that block signaling pathways will be used in the clinic. The well-documented cross-talk between the key pathways that regulate cell cycle traversal, apoptosis, and processes such as angiogenesis and metastasis strongly suggests that combinations of new agents targeting one or more of these critical regulating pathways will enhance the efficacy of cancer therapy.

APPENDIX
Collaborators From the University of California San Diego: Gordon Sato, Hideo Masui, Gordon Gill, Tomo Kawamoto, and Denry Sato. From the Memorial Sloan-Kettering Cancer Center: Jose Baselga, Larry Norton, Andy Koff, Xipu Wu, Ding Peng, Steven Larson, and C. Divgi. From the University of Texas M.D. Anderson Cancer Center: Waun Ki Hong, Dong Shin, Zhen Fan (and Memorial Sloan Kettering), Rakesh Kumar (and Memorial Sloan-Kettering), Colin Dinney, and Robert Radinsky. From ImClone Systems, Inc: Harlan Waksal. From Naples: Fortunato Ciardiello and Giampaolo Tortora.

The appendix listing Dr Mendelshon’s former and current collaborators and trainees is available online at www.jco.org.

	ACKNOWLEDGMENTS

 
I would like to thank my mentors and collaborators. My research training began in the laboratory of Dr. James D. Watson in 1956. I was his first undergraduate student at Harvard College, and the term molecular biology was novel at that time. It is amazing what has happened in less than 50 years. Dr John Paul at the University of Glasgow taught me the mysteries of cell culture during my year as a Fulbright Scholar. Dr Byron Waksman at the Massachusetts General Hospital taught me experimental immunology. Dr Norman Salzman at the National Institutes of Health introduced me to the 1965 version of molecular biology, which had exploded in techniques and possibilities. Dr Stuart Kornfeld introduced me to translational laboratory research during my fellowship at Washington University. And the most important person to add to this list is Anne Mendelsohn, my wife since 1963, who is a fabulous mother and partner in everything we have done together at University of California San Diego, Memorial Sloan-Kettering Cancer Center, and The University of Texas M.D. Anderson Cancer Center.

Thank you very much for the honor of the Karnofsky Award.

	NOTES

 
The author is a director and has financial interests in ImClone Systems, Inc, New York, NY, which has licensed the antibody C225 from the University of California. The author has never treated a patient with C225.

	REFERENCES

TOP INTRODUCTION RATIONALE MECHANISMS OF ACTION RESULTS OF CLINICAL TRIALS FUTURE DIRECTIONS REFERENCES

 
1. Kawamoto TK, Sato JD, Le A, et al: Growth stimulation of A431 cells by epidermal growth factor: Identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A 80: 1337-1341, 1983[Abstract/Free Full Text]

2. Sato JD, Kawamoto T, Le AD, et al: Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med 1: 511-529, 1983[Medline]

3. Gill GN, Kawamoto T, Cochet C, et al: Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259: 7755-7760, 1984[Abstract/Free Full Text]

4. Cohen S: Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new born animal. J Biol Chem 237: 1555-1562, 1962[Free Full Text]

5. Cohen S, Carpenter G, King L Jr: Epidermal growth factor receptor-kinase interactions: Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. J Biol Chem 255: 4834-4842, 1980[Abstract/Free Full Text]

6. Barnes D, Sato G: Serum-free cell culture: A unifying approach. Cell 22: 649-655, 1980[CrossRef][Medline]

7. Sporn MB, Todaro GJ: Autocrine secretion and malignant transformation of cells. N Engl J Med 303: 878-880, 1980[Medline]

8. Ozanne B, Richards CS, Hendler F: Over-expression of the EGF receptor is a hallmark of squamous cell carcinomas. J Pathol 149: 9-14, 1986[CrossRef][Medline]

9. Cooper JA, Hunter T: Similarities and differences between the effect of epidermal growth factor and Rous sarcoma virus. J Cell Biol 91: 878-883, 1981[Abstract/Free Full Text]

10. Chinkers M, Cohen S: Purified EGF receptor-kinase interacts specifically with antibodies to Rous sarcoma virus transforming protein. Nature 290: 516-519, 1981[CrossRef][Medline]

11. Erickson E, Shealy DJ, Erickson RL: Evidence that viral transforming gene products and epidermal growth factor stimulate phosphorylation of the same cellular protein with similar specificity. J Biol Chem 256: 11381-11384, 1981[Abstract/Free Full Text]

12. Downward J, Yarden Y, Mayes E, et al: Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences. Nature 307: 521-527, 1984[CrossRef][Medline]

13. Lin CR, Chen WS, Kruiger W, et al: Expression cloning of human EGF receptor complementary DNA: Gene amplification and three related messenger RNA products in A431 cells. Science 224: 843-848, 1984[Abstract/Free Full Text]

14. Ullrich A, Coussens L, Hayflick JS, et al: Human epidermal growth factor receptor cRNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309: 418-425, 1984[CrossRef][Medline]

15. Xu YH, Ishii S, Clark AJ, et al: Human epidermal growth factor receptor cDNA is homologous to a variety of RNAs overproduced in A431 carcinoma cells. Nature 309: 806-810, 1984[CrossRef][Medline]

16. Masui H, Kawamoto T, Sato JD, et al: Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44: 1002-1007, 1984[Abstract/Free Full Text]

17. Drebin JA, Link VC, Weinberg RA, et al: Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc Natl Acad Sci U S A 83: 9129-9133, 1986[Abstract/Free Full Text]

18. Hudziak RM, Lewis GD, Winget M, et al: p185^HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol 9: 1165-1172, 1989[Abstract/Free Full Text]

19. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707-712, 1989[Abstract/Free Full Text]

20. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-792, 2001[Abstract/Free Full Text]

21. Goldstein NI, Prewett M, Zuklys K, et al: Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1: 1311-1318, 1995[Abstract]

22. Waterfield MD, Mayes ELV, Stroobant P, et al: A monoclonal antibody to the human epidermal growth factor receptor. J Cell Biochem 20: 149-161, 1982[CrossRef][Medline]

23. Yang XD, Jia XC, Corvalan JR, et al: Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res 59: 1236-1243, 1999[Abstract/Free Full Text]

24. Bier H, Hoffmann T, Hauser U, et al: Clinical trial with escalating doses of the antiepidermal growth factor receptor humanized monoclonal antibody EMD 72 000 in patients with advanced squamous cell carcinoma of the larynx and hypopharynx. Cancer Chemother Pharmacol 47: 519-524, 2001[CrossRef][Medline]

25. Crombet T, Osorio M, Cruz T, et al: Use of the anti-EGFR antibody h-R3 in combination with radiotherapy in the treatment of advanced head and neck cancer. Proc Am Soc Clin Oncol 21: 14a, 2002 (abstr 53)

26. Negri DR, Tosi E, Valota O, et al: In vitro and in vivo stability and anti-tumour efficacy of an anti- EGFR/anti-CD3 F(ab')2 bispecific monoclonal antibody. Br J Cancer 72: 928-933, 1995[Medline]

27. Pfister DG, Lipton A, Belt R, et al: A phase I trial of the epidermal growth factor receptor (EGFR)-directed bispecific antibody (BsAB) MDX-447 in patients with solid tumors. Proc Am Soc Clin Oncol 18: 433a, 1999 (abstr 1667)

28. Goldstein J, Graziano RF, Sundarapandiyan K, et al: Cytolytic and cytostatic properties of an anti-human Fc gammaRI (CD64) x epidermal growth factor bispecific fusion protein. J Immunol 158: 872-879, 1997[Abstract]

29. Levitzki A, Gazit A: Tyrosine kinase inhibition: An approach to drug development. Science 267: 1782-1788, 1995[Abstract/Free Full Text]

30. Fry DW, Kraker AJ, McMichael A, et al: A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265: 1093-1095, 1994[Abstract/Free Full Text]

31. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6: 2053-2063, 2000[Abstract/Free Full Text]

32. Albanell J, Rojo F, Averuch S, et al: Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20: 110-124, 2002[Abstract/Free Full Text]

33. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of the OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19: 3267-3279, 2001[Abstract/Free Full Text]

34. Perez-Soler R, Chachoua A, Huberman M, et al: A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy in patients (pts) with advanced. EGFR-expressing, non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20: 310a, 2001 (abstr 1235)

35. Muren JR, Papadimitrakopoulou VA, Sizer KC, et al: A phase I dose-escalating study to evaluate the biological activity and pharmacokinetics of PKI166, a novel tyrosine kinase inhibitor, in patients with advanced cancers. Proc Am Soc Clin Oncol 21: 95a, 2002 (abstr 377)

36. Torrance CJ, Jackson PE, Montgomery E, et al: Combination chemoprevention of intestinal neoplasia. Nat Med 6: 1024-1028, 2000[CrossRef][Medline]

37. Rusnak DW, Affleck K, Gilmer TM, et al: The effects of the novel EGFR/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and transformed cell lines. Proc Am Assoc Cancer Res 42: 4309a, 2001 (abstr)

38. Zinner RG, Nemunaitis J, Donato NJ, et al: A phase I clinical and biomarker study of the novel pan-erB tyrosine kinase inhibitor, CI-1033, in patients with solid tumors. Clin Cancer Res 7: 566a, 2001 (abstr, suppl)

39. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100: 57-70, 2000[CrossRef][Medline]

40. Albanell J, Codony-Servat J, Rojo F, et al: Activated extracellular signal-regulated kinases: Association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-EGF receptor treatments. Cancer Res 61: 6500-6510, 2001[Abstract/Free Full Text]

41. Wu X, Fan Z, Masui H, et al: Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 95: 1897-1905, 1995

42. Huang SM, Li J, Armstrong EA, et al: Modulation of radiation response and tumor-induced angiogenesis following EGFR inhibition by ZD1839 (’Iressa’)¹. Cancer Res 62: 4300-4306, 2002[Abstract/Free Full Text]

43. Wu X, Rubin M, Fan Z, et al: Involvement of p27^KIP1 in G₁ arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene 12: 1397-1403, 1996[Medline]

44. Mendelsohn J: Blockade of receptors for growth factors: An anti-cancer therapy. Clin Cancer Res 6: 747-753, 2000[Free Full Text]

45. Lehmann K, Janda E, Pierreux CE, et al: Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: A mechanism leading to increased malignancy in epithelial cells. Genes Dev 14: 2610-2622, 2000[Abstract/Free Full Text]

46. Massague J: How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1: 169-178, 2000[CrossRef][Medline]

47. Mandal M, Adam L, Mendelsohn J, et al: Nuclear targeting of Bax during epidermal growth factor receptor-induced apoptosis in colorectal cancer cells. Oncogene 17: 999-1007, 1998[CrossRef][Medline]

48. Liu B, Fang M, Schmidt M, et al: Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer 82: 1991-1999, 2000[CrossRef][Medline]

49. Petit AM, Rak J, Hung MC, et al: Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: Angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol 151: 1523-1530, 1997[Abstract]

50. Perrotte P, Matsumoto T, Inoue K, et al: Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5: 257-265, 1999[Abstract/Free Full Text]

51. Bruns CJ, Harbison MT, Davis DW, et al: Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by anti-angiogenic mechanisms. Clin Cancer Res 6: 1936-1948, 2000[Abstract/Free Full Text]

52. Baker CH, Kedar D, McCarthy MF, et al: Blockade of epidermal growth factor receptor signaling on tumor cells and tumor associated endothelial cells for therapy of human carcinomas. Am J Pathol (in press)

53. Aboud-Pirak E, Hurwitz E, Pirak ME, et al: Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J Natl Cancer Inst 80: 1605-1611, 1988[Abstract/Free Full Text]

54. Fan Z, Baselga J, Masui H, et al: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53: 4637-4642, 1993[Abstract/Free Full Text]

55. Baselga J, Norton L, Masui H, et al: Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 85: 1327-1333, 1993[Abstract/Free Full Text]

56. Baselga J, Norton L, Coplan K, et al: Antitumor activity of paclitaxel in combination with anti-growth factor receptor monoclonal antibodies in breast cancer xenografts. Proc Am Assoc Cancer Res 35: 380, 1994 (abstr A2262)

57. Sirotnak FM, Zakowski MF, Miller VA, et al: Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6: 4885-4892, 2000[Abstract/Free Full Text]

58. Ciardiello F, Bianco R, Damiano V, et al: Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin Cancer Res 5: 909-916, 1999[Abstract/Free Full Text]

59. Ciardiello F, Caputo R, Bianco R, et al: Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7: 1459-1465, 2001[Abstract/Free Full Text]

60. Shin DM, Donato NJ, Perez-Soler R, et al: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 7: 1204-1213, 2001[Abstract/Free Full Text]

61. Hong WK, Arquette M, Nabell L, et al: Efficacy and safety of the anti-epidermal growth factor antibody (EGFR) IMC-C225, in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 20: 224a, 2001 (abstr 895)

62. Kies MS, Arquette MA, Nabell L, et al: Final report of the efficacy and safety of the anti-epidermal growth factor antibody Erbitux (IMC-C225), in combination with cisplatin in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN) refractory to cisplatin containing chemotherapy. Proc Am Soc Clin Oncol 21: 232a, 2002 (abstr 925)

63. Baselga J, Trigo JM, Bourhis J, et al: Cetuximab (C225) plus cisplatin/carboplatin is active in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) progressing on a same dose and schedule platinum-based regimen. Proc Am Soc Clin Oncol 21: 226a, 2002 (abstr 900)

64. Burtness BA, Li Y, Flood W, et al: Phase III trial comparing cisplatin (C) + placebo to C + anti-epidermal growth factor antibody (EGF-R) C225 in patients (pts) with metastatic/recurrent head & neck cancer (HNC). Proc Am Soc Clin Oncol 21: 226a, 2002 (abstr 901)

65. Fukuoka M, Yano S, Giaccone G, et al: Final results from a phase II trial of ZD1839 (‘Iressa’) for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol 21: 298a, 2002 (abstr 1188)

66. Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD1839 (‘Iressa’) in advanced non-small cell lung cancer (NSCLC) patients who failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 21: 292a, 2002 (abstr 1166)

67. Kim ES, Mauer AM, Fossella FV, et al: A phase II study of Erbitux (IMC-C225), an epidermal growth factor receptor (EGFR) blocking antibody, in combination with docetaxel in chemotherapy refractory/resistant patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21: 293a, 2002 (abstr 1168)

68. Prewett MC, Hooper AT, Bassi R, et al: Enhanced antitumor activity of anti-epidermal growth factor receptor monoclonal antibody IMC-C225 in combination with irinotecan (CPT-11) against human colorectal tumor xenografts. Clin Cancer Res 8: 994-1003, 2002[Abstract/Free Full Text]

69. Saltz L, Rubin M, Hochster H, et al: Cetuximab (IMC-225) plus irinotecan (CPT-11) is active in CPT-11-refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Proc Am Soc Clin Oncol 20: 3a, 2001 (abstr 7)

70. Lenferink AE, Simpson JF, Shawver LK, et al: Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice. Proc Natl Acad Sci U S A 97: 9609-9614, 2000[Abstract/Free Full Text]

71. Moasser M, Basso A, Averbuch S, et al: The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61: 7184-7188, 2001[Abstract/Free Full Text]

72. Torrance CJ, Jackson PE, Montgomery E, et al: Combinatorial chemoprevention of intestinal neoplasia. Nat Med 6: 1024-1028, 2000

73. Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59: 1935-1940, 1999[Abstract/Free Full Text]

74. Milas L, Mason K, Hunter N, et al: In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 6: 701-708, 2000[Abstract/Free Full Text]

75. Robert F, Ezekiel MP, Spencer SA, et al: Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 19: 3234-3243, 2001[Abstract/Free Full Text]

76. Cohen RB, Falcey JW, Paulter VJ, et al: Safety profile of the monoclonal antibody (MoAb) IMC-C225, an anti-epidermal growth factor receptor (EGFr) used in the treatment of EGFr-positive tumors. Proc Am Soc Clin Oncol 19: 474a, 2000 (abstr 1862)

77. Bos M, Mendelsohn J, Kim YM, et al: PD 153035, a tyrosine kinase inhibitor, prevents receptor activation and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor in a dose and receptor number dependent manner. Clin Cancer Res 3: 2099-2106, 1997[Abstract]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				D. A Frieze and J. S McCune Current Status of Cetuximab for the Treatment of Patients with Solid Tumors Ann. Pharmacother., February 1, 2006; 40(2): 241 - 250. [Abstract] [Full Text] [PDF]

				T. G. Johns, R. B. Luwor, C. Murone, F. Walker, J. Weinstock, A. A. Vitali, R. M. Perera, A. A. Jungbluth, E. Stockert, L. J. Old, et al. Antitumor efficacy of cytotoxic drugs and the monoclonal antibody 806 is enhanced by the EGF receptor inhibitor AG1478 PNAS, December 23, 2003; 100(26): 15871 - 15876. [Abstract] [Full Text] [PDF]

				J. Mendelsohn and J. Baselga Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer J. Clin. Oncol., July 15, 2003; 21(14): 2787 - 2799. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mendelsohn, J. Search for Related Content PubMed PubMed Citation Articles by Mendelsohn, J. Social Bookmarking                            What's this?