With the understanding of the mechanism of
malignant transformation has come the knowledge that oncogene products are
frequently growth factors, growth factor receptors, or elements of growth factor
signal-transduction pathways. Overexpression of the components of these
signal-transduction pathways can lead to the development and propagation of
malignancies. In addition, human cells exhibit complex responses to DNA damage,
including activation of genes involved in cell-cycle arrest, DNA repair, and
apoptosis. Recent findings suggest that the cellular response to DNA damage is
markedly impaired by deprivation of essential growth factors or by blockage of
growth-factor receptors, which suggests that these pathways contribute to the
ineffectiveness of chemotherapy and radiation.[1,2] Thus, specific blockade of
these pathways in tumor cells may be attractive targets for new cancer
therapies, since inhibiting these pathways may induce tumor stasis and/or
regression and increase the cytotoxic effects of chemotherapy and radiation.
The ErbB family of growth-factor receptors is well characterized
and has generated significant interest as a target for cancer therapeutics. The
family consists of epidermal growth factor receptor (EGFR), HER2, HER3, and
HER4, and at least 10 ligands that bind and activate family members.
Ligand-receptor binding results in receptor dimerization with the same
or different family member, autophosphorylation, kinase activation, and the
generation of binding sites for downstream adaptor molecules and second
Because family members can be activated by multiple ligands and
ligand-receptor expression determines homo/heterodimerization between receptors
as well as rate of receptor internalization and degradation, the efficiency and
diversity of signal transduction through these receptor complexes is remarkable.
Activation of this family of growth-factor receptors influences cell
proliferation, survival, motility, adhesion, invasion, and angiogenesis.
Preclinical and clinical data support the involvement of the ligands’
transforming growth factor-alpha and epidermal growth factor and EGFR in the
formation and progression of human cancers. Hyperactive receptor signaling
promotes deregulated cell growth and subsequent development of malignancy.
EGFR is overexpressed in a significant proportion of human
cancers such as breast, lung, and head and neck carcinomas, and
glioblastomas.[4,5] In addition, several studies suggest a correlation between
receptor and/or ligand expression and poor prognosis. In some studies, EGFR
overexpression was associated with poorer prognosis in bladder, head and neck,
esophageal, non-small-cell lung, and breast cancer patients.[6-10] Most
importantly, EGFR inhibition in EGFR-expressing cancer cells leads to cell cycle
arrest, apoptosis, tumor stasis, and even tumor regression in preclinical
models.[3,11] Inhibitors of EGFR appear to work additively and/or
synergistically with standard cytotoxic agents and radiotherapy.
A number of modalities are being developed to target the ErbB
family. These include antibodies to the extracellular domain of the receptors,
small molecules that reversibly or irreversibly inhibit receptor
autophosphorylation by inhibiting ATP binding, and antisense oligonucleotides.
Among these pharmacologic strategies, both antibodies and small molecules
directed toward EGFR are currently in clinical development (Table
1). However, only the small molecule ZD1839 (Iressa) and the antibody C225
are presently in phase III trials (see trials).
Given the success of trastuzumab (Herceptin), a humanized,
anti-HER2 murine monoclonal antibody, directed against the extracellular domain
of HER2, it is not surprising that a similar approach targeting EGFR is
underway. C225, a human/mouse chimeric antibody, binds to the EGFR extracellular
domain blocking EGF-ligand binding. In vitro, this antibody blocks
ligand-dependent proliferation of tumor cell lines and can induce tumor
regression in xenografts. C225 potentiates the effects of ionizing radiation
and, similar to trastuzumab, enhances the activity of doxorubicin and
Phase I trials of C225 evaluating single-dose and multi-dose
schedules have been reported. In neither study was the maximum tolerated
dose reached. In the single dose schedule, patients with various
EGFR-overexpressing tumors received 5 to 100 mg/m2 intravenously over
30 minutes. Toxicities included fever, chills, fatigue, hepatic transaminase
elevation, nausea, and acneiform skin rash. Receptor-saturating levels were
obtained for 7 days. Two patients with head and neck cancer had minor responses.
No serious toxicities were seen in patients receiving C225 weekly and antibody
doses in the range of 200 to 400 mg/m2 were associated with complete
saturation of systemic clearance. Coadministration of cisplatin at 60 mg/m2
once every 4 weeks with C225 doses of 5 to 400 mg/m2 did not alter
C225 clearance. Antibodies against C225 were detected in only one patient, and
C225-associated toxicity was minimal. Of 13 patients treated with antibody doses
of ³ 50 mg/m2 with cisplatin, 9 completed
12 weeks of therapy, and two partial responses were observed. Concurrent
treatment with C225 and radiation in patients with head and neck carcinoma did
not enhance radiation-induced toxicity, and all the patients in this phase I
study achieved a response. Currently, a phase III study to determine the
additional benefit of C225 to radiation is being evaluated in this patient
Antibodies can exert a therapeutic effect by hindering
receptor-ligand binding or receptor-receptor dimerization. They may also induce
antibody-mediated cellular cytotoxicity. However, there are potential
disadvantages to the use of antibodies as therapeutic modalities. Antibodies are
bulky, which may result in inefficient treatment delivery in the setting of
central nervous system malignancies. They bind to the extracellular domain of
the receptor and therefore will be inactive against the truncated forms of the
molecule that may be present in some percentage of tumors. Finally, antibodies
have the potential for generating an immunologic response that may hinder
repeated treatment. Despite these theoretical disadvantages, the anti-EGFR
antibody C225 has been well tolerated and has shown promising results in early
Small molecule inhibitors of the intracellular tyrosine kinase
domain of EGFR are also under clinical evaluation.[3,17,18] Currently available
EGFR inhibitors belong to three chemical series: 4-anilinoquinazolines,
4-[ar(alk)ylamino] pyridopyrimidines, and 4-phenylaminopyrrolo-pyrimidines. Two
quinazolines that have shown promising antitumor activity in early clinical
trials are ZD1839 and OSI-774 (formerly CP-358, 774). These small molecules
competitively inhibit ATP binding to EGFR, hindering autophosphorylation, and
induce tumor stasis and even tumor regression in some tumor xenograft models.
In addition to their shared mechanism of action, these agents
are also administered orally on chronic schedules and have a similar spectrum of
toxicity, with diarrhea and skin rash being most common. More recently, potent,
irreversible inhibitors of EGFR kinases have been developed such as CI-1033,
which inhibits all four EGFR family members. This compound covalently binds to a
cysteine residue near the ATP binding site. Whether irreversible inhibition will
result in an improved therapeutic index or will remove the need for continuous
dosing will require further clinical study.
ZD1839 is an anilinoquinazoline that acts as a potent and
specific inhibitor of EGFR tyrosine kinase activity by competing with adenosine
triphosphate for its binding site on the intracellular domain of the receptor.
The IC50 of ZD1839 using enzyme extracted from A431 human squamous vulval cell
line was 0.023 to 0.079 mM. It is approximately 100-fold less active
against ErbB2 kinase and has little or no enzyme inhibitory activity against
several other tyrosine and serine-threonine kinases tested. ZD1839 has antitumor
activity in a broad range of human tumor xenografts with both tumor stasis and
regression seen in xenograft models. However, rapid regrowth of tumors was
generally observed when the drug was discontinued, suggesting the need for
Two trials are assessing escalating doses of ZD1839 administered
on a continuous daily schedule. Dose-limiting toxicity has not been reached at
dose levels of 600 and 800 mg/d. The most frequent adverse events were grade
1 or 2 skin rash, diarrhea, nausea, and vomiting. Grade 3 adverse events
included diarrhea, skin rash, increased hepatic transaminases, nausea, and
vomiting. Skin toxicity consisted primarily of grade 1 or 2 pustular or
acne-like lesions with occasional erythema, or dry skin. The rash was usually
located on the face, with involvement of the upper torso at higher doses, and
resolved rapidly after discontinuation of the drug. Nausea and/or emesis
occurred infrequently and was mild to moderate in severity. Oral doses of 250
and 500 mg/d in combination with standard chemotherapy are being evaluated in
ongoing phase III placebo-controlled studies in patients with locally advanced
non-small-cell lung cancer.
The Cancer Therapy Evaluation Program (CTEP) of the National
Cancer Institute (NCI) is currently sponsoring clinical trials of ZD1839 in
glioblastoma, squamous cell carcinoma of the head and neck, renal cell
carcinoma, transitional cell carcinoma, colorectal carcinoma, and locally
advanced non-small-cell lung carcinoma. Other studies are planned in ovarian
carcinoma, endometrial carcinoma, and mesothelioma. Research goals include
defining optimal combinations with conventional chemotherapeutic agents and with
radiation therapy, determining the best therapy candidates, and expanding
clinical trials to other tumor types. Details of these trials can be found
through the National Cancer Institute’s PDQ Clinical Trials Database (http://cancernet.nci.nih.gov/trialsrch.shtml)
available on the Internet through CancerNet, an NCI website that features
interactive tools for online searching.
1. Kastan MB, Canman CE, Leonard CJ, et al: P53, cell cycle
control and apoptosis: Implications for cancer. Cancer Metastasis Rev 14:3-15,
2. Lichter AS, Lawrence TS: Recent advances in radiation
oncology. N Engl J Med 332:371-379, 1995.
3. Woodburn JR:The epidermal growth factor receptor and its
inhibition in cancer therapy. Pharmacol Ther 82(2-3):241-250, 1999.
4. Pegram MD, Pauletti G, Slamon DJ, et al: HER-2/neu as a
predictive marker of response to breast cancer therapy. Breast Cancer Res Treat
5. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth
factor-related peptides and their receptors in human malignancies. Crit Rev
Oncol Hematol 19:183-232, 1995.
6. Diedrich U, Lucius J, Baron E, et al: Distribution of
epidermal growth factor receptor gene amplification in brain tumours and
correlation to prognosis. J Neurol 242:683-688, 1995.
7. Giatromanolaki A, Koukourakis MI, O’Byrne K, et al:
Non-small cell lung cancer: c-ErbB-2 overexpression correlates with low
angiogenesis and poor prognosis. Anticancer Res 16:3819-3825, 1996.
8. Maurizi M, Almadori G, Ferrandina G, et al: Prognostic
significance of epidermal growth factor receptor in laryngeal squamous cell
carcinoma. Br J Cancer 74:1253-1257, 1996.
9. Dong M, Nio Y, Guo KJ, et al: Epidermal growth factor and its
receptor as prognostic indicators in Chinese patients with pancreatic cancer.
Anticancer Res 18:4613-4619, 1998.
10. Ohsaki Y, Tanno S, Fujita Y, et al: Epidermal growth factor
receptor expression correlates with poor prognosis in non-small cell lung cancer
patients with p53 overexpression. Oncol Rep 7:603-607, 2000.
11. Gibbs JB: Anticancer drug targets: Growth factors and growth
factor signaling. J Clin Invest 105:9-13, 2000.
12. Fortunato C, Caputo R, et al: Potentiation of cytotoxic
drugs activity in human cancer cells by ZD-1839 (Iressa), an EGFR-selective
tyrosine kinase inhibitor. Proc Ann Meet Am Assoc Cancer Res 41:A3075, 2000.
13. Huang SM, Bock JM, Harari PM, et al: Epidermal growth factor
receptor blockade with C225 modulates proliferation, apoptosis, and
radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res
14. Prewett M, Rockwell P, Rockwell RF, et al: The biologic
effects of C225, a chimeric monoclonal antibody to the EGFR, on human prostate
carcinoma. J Immunother Emphasis Tumor Immunol 19:419-27, 1996.
15. Baselga J, Pfister D, Cooper MR, et al: Phase I studies of
anti-epidermal growth factor receptor chimeric antibody C225 alone and in
combination with cisplatin. J Clin Oncol 18:904-914, 2000.
16. Bonner JA, Ezekiel MP, Robert F, et al: Continued response
following treatment with IMC-C225, an EGFR MoAb, combined with RT in advanced
head and neck malignancies (abstract 5F). Proc Am Soc Clin Oncol 19:4a, 2000.
17. Fry DW: Inhibition of the epidermal growth
factor receptor family of tyrosine kinases as an approach to cancer
chemotherapy: progression from reversible to irreversible inhibitors. Pharmacol
Ther 82(2-3):207-218, 1999.
18. Traxler P, Furet P: Strategies toward the design of novel
and selective protein tyrosine kinase inhibitors. Pharmacol Ther
19. Woodburn JR, Barker AJ, et al: ZD1839, an epidermal growth
factor tyrosinde kinase inhibitor selected for clinical development (meeting
abstract). Proc Ann Meet Am Assoc Cancer Res 38:A4251, 1997.
20. Baselga J, LoRusso P, et al: A
pharmacokinetic/pharmacodynamic trial of ZD1839 (Iressa), a novel oral epidermal
growth factor receptor tyrosine kinase (EGFR-TK) inhibitor, in patients with 5
selected tumor types (a phase I/II trial of continuous once-daily treatment)
(meeting abstract A29). Proceedings of the 1999 AACR-NCI-EORTC International
Conference on Molecular Targets and Cancer Therapeutics. Washington, DC, 1999.