| | Epidermal growth factor family receptors and inhibitors: Radiation response modulators☆☆☆Abstract Growing evidence suggests that epidermal growth factor family receptors (HERs) play a significant role in radiation response. EGFR expression levels and activation by ligand correlate with radioresistance, and exogenous HER2 expression alters radiation response. Preclinical studies of anti-EGFR anti-HER2 antibodies, and kinase inhibitors that inhibit EGFR, both EGFR and HER2, or all 4 family members show potential for clinical radiosensitization. Early-phase clinical trials of the anti-EGFR antibody, C225, prove the combination of C225 and radiotherapy to be well tolerated and promising. A phase 3 randomized trial in head and neck cancer is underway, and clinical investigation of other HER inhibitors is in progress. The mechanisms(s) of radiation response modulation by HERs appear complex and diverse. Signal transduction initiated by receptor activation promotes survival and proliferation after ionizing radiation, and HER inhibitors affect cellular responses to ionizing radiation (IR) in diverse ways, including inducing apoptosis, cell cycle arrest, and impeding DNA repair. HER signaling and inhibition also affect tumor-stroma interactions, particularly angiogenesis and endothelial survival after IR. Further investigation of the radiation response modulation by EGFR family members and their inhibitors will lead to optimization of this promising therapeutic approach. Copyright 2003, Elsevier Science (USA). All rights reserved.
The epidermal growth factor receptor family consists of 4 transmembrane receptor tyrosine kinases; EGFR, HER2 (erbB-2), HER3 (erbB-3), and HER4 (erbB-4), whose function is to transmit extracellular cues directing proliferation, differentiation, and survival responses. The receptors are physiologically activated by ligand binding to the extracellular domain of a receptor monomer that leads to dimerization with the same or another family member. Two large ligand families (EGF and heregulin) activate various combinations of the receptors. Once the receptors have dimerized, the cytoplasmic domains, which contain tyrosine kinase activity, phosphorylate themselves and their partners on key tyrosine residues. Tyrosine phosphorylation induces recruitment of proteins that activate signaling cascades, including the PLC-gamma, PI3-K, ras-MAPK, and STAT pathways. The end result depends on which signals are activated, as well as the duration and intensity of signaling. These factors are affected by receptor downregulation and turnover, which, in turn, depends on composition of the receptor dimer and activating ligand.1
Epithelial tumors frequently dysregulate the complex balance of HER signaling by escaping regulatory control through a variety of mechanisms (Fig 1).
Autocrine or paracrine production of activating ligands enables tumor cells to activate their own receptors. Inappropriate activation of receptors may also result from overexpression. Overexpression of HER2 because of gene amplification is thought to lead to HER2:HER2 homodimerization and ligand-independent activation. Ligand-independent activation also results from rearrangements during gene amplification or splicing resulting in loss of regulatory domains. For example, EGFRvIII, present in a subset of gliomas, is a truncated EGFR that has lost its ligand-binding domain, rendering it unresponsive to ligand stimulation but constitutively activated. Dysregulation via any of these mechanisms results in inappropriate activation of downstream proliferative and survival signals.
Consistent with the variety of mechanisms of EGFR family member dysregulation, several approaches have been used for inhibition of HERs. C225 (Cetuximab; Erbitux, Imclone, NJ) is an anti-EGFR antibody that blocks binding of EGF ligands to the EGFR, inhibiting EGFR activation, particularly activation because of autocrine stimulation.2 Herceptin (Trastuzumab; Genentech, San Francisco, CA) is an anti-HER2 antibody. Although the mechanism of action is not entirely clear, the preponderance of evidence suggests that Herceptin binds to HER2 homodimers that occur when HER2 is overexpressed to the high levels seen with gene amplification and accelerates downregulation of the receptors.3 Small molecule tyrosine kinase inhibitors bind to the ATP-binding site within the cytoplasmic domain of the receptor and may be specific for an individual receptor, such as Iressa (ZD1389; Astra-Zeneca, Wilmington, DE), or inhibit multiple family members, eg, CI-1033 (Pfizer Global Research and Development, Ann Arbor, MI) and GSK2016 (Glaxo-Wellcome, Research Triangle Park, NC).4 This selection of agents with different mechanisms of inhibition provides an opportunity to choose the most appropriate inhibitor for a particular pathophysiology. For instance, receptor activation because of autocrine stimulation would be optimally inhibited by C225, whereas HER2 overexpression by Herceptin, and EGFRvIII by kinase inhibitors (Fig 1).
EGFR and radioresistance  Clinical studies associate EGFR overexpression with radioresistance. In a study of 170 patients treated with radiotherapy for glioblastomas, radiographic response correlated with EGFR expression; 33% of tumors with no detectable expression of EGFR as measured by immunohistochemistry responded clinically versus 18% with intermediate and 9% with strong expression of EGFR.5 In another study, clinical response of head and neck cancers to primary radiation therapy correlated with EGFR overexpression and activation of the PI3-K/Akt downstream signal transduction pathway.6 In a series of 38 patients, all 7 local recurrences occurred in patients whose tumors showed both phosphorylated Akt and EGFR overexpression (P = .04). In cell lines established from head and neck cancers, a correlation also exists between relative radioresistance and increasing levels of EGFR expression.7 Although a direct causal role has not been established for EGFR, expression of v-erbB, the oncogenic homologue of EGFR, in 32D murine hematopoietic cells renders the cells resistant to low-dose rate ionizing radiation.8 In vitro studies further indicate that EGFR plays a role in radiation response. EGFR activation by EGF induces radioresistance in A431 cells, a human vulvar carcinoma cell line that overexpresses EGFR at high levels because of gene amplification, as well as in MCF7 human breast cancer cells that express normal levels of EGFR.9, 10 However, EGFR stimulation by EGF has also been shown to increase radiosensitivity.11, 12 Activation of EGFR by ionizing radiation (IR) may also contribute to radioresistance. A single 1 to 5 Gy exposure results in a modest, rapid, transient increase in activation of EGFR and downstream signal transduction pathways.13, 14 Furthermore, a secondary, delayed activation of EGFR in response to IR results from release of TGF-alpha after IR-induced cleavage of the membrane bound precurser, which contributes to clonogenic survival.15 Further evidence that EGFR may contribute to survival and regrowth of tumor cells after fractionated radiotherapy comes from studies of cells resistant to 60 Gy in 2 Gy fractions (split into 3 courses). The resistant lines had upregulated expression of TGF-alpha, an EGFR ligand.16 Similarly, subclones that resumed proliferation after a prolonged arrest after ten 3 Gy fractions delivered over 2 weeks had a high incidence of constitutive EGFR activation.17 These studies using clinically relevant dose and fractionation schemes suggest a role for EGFR activation in tumor recurrence. HER2 overexpression correlates with ipsilateral breast tumor recurrence after conservative surgery and radiotherapy.18 Furthermore, a causal role for HER2 as a mediator of radioresistance has been supported by studies showing that exogenous HER2 expression renders cells radioresistant compared with the nonoverexpressing parental cells.19, 20 Little is known about the effect, if any, of HER3 or HER4 activation on radiation response, but studies are underway. It is likely that they too will play a role in radiation response and, like EGFR and HER2, may also be relevant targets for sensitization. Preclinical studies of HER inhibitors as radiosensitizers Because EGFR family receptors appear to be radiation response modulators, HER inhibitors are potential radiosensitizers. A number of preclinical studies have supported clinical development of combined therapy with EGFR, HER2 inhibitors, and radiation.21 C225 has been investigated in several settings. In EGFR overexpressing head and neck cancer cell lines, C225 modestly but reproducibly enhanced cell kill in single-dose clonogenic survival assays. In vivo studies showed tumor regrowth delay with either radiation or C225 but complete tumor regression for 3 months with combined therapy.22 Optimal antitumor effect is seen when C225 is delivered both before and after IR. Using A431 xenografts, tumor cure (disappearance of tumor lasting at least 120 days) and regrowth delay were best with C225 given 6 hours before plus 3 and 6 days after IR.23 Radiosensitization by C225 improved survival in an orthotopic glioma model.24 Herceptin is an antireceptor antibody like C225 but is directed against HER2. In preclinical studies, Herceptin has been shown to reverse the radioresistance of MCF7/HER2 cells (MCF7 breast cancer cells in which HER2 has been expressed to high levels), as measured by single-dose, colony-forming assay. Herceptin also promoted remission of MCF7-HER2 xenografts.20 Consistent with its selectivity for HER2 overexpressing cells, Herceptin does not sensitize H16N2 or MCF10A human mammary epithelial cells that express normal levels of HER2 (Sartor, unpublished data, 2000). In A431 and H226 cells, a non–small-cell lung cancer line with moderately high EGFR expression, additive to synergistic growth inhibition was seen with Iressa delivered 24 hours before 4 Gy.25 In a colon cancer (LoVo) xenograft model, Iressa given before a single 5-Gy fraction or three 2-Gy fractions caused significant growth delay and tumor regression compared with control tumors treated with radiation alone. The effect was more pronounced with fractionated than with single-dose treatment.26 In a variety of xenograft models with varying degrees of EGFR overexpression, a fractionated course of radiation to a total dose of 40 Gy was tolerated well in combination with ZD1839 given at MTD (150 mg/kg). Combined therapy caused marked regression compared with control, regardless of tumor type.27 Radiosensitization as measured by clonogenic survival has also been reported for EGFR overexpressing glioma cells.28 Although Iressa is relatively specific for EGFR kinase inhibition, heterodimerization of the receptors in some contexts causes Iressa to inhibit signaling from other family members because Iressa causes inactive EGFR:HER2 or EGFR:HER3 heterodimers.29 The tumor profile of receptor expression may also affect radiosensitization by Iressa; overexpression of HER2 interferes with EGFR kinase inhibition by Iressa.30 Because of the complex interactions between HERs, sensitization in some cases may be most effective with inhibitors that target multiple family members. CI-1033 inhibits the kinase activity of all EGFR family members relatively equally and shows strong sensitization of breast cancer cell lines that have aberrant EGFR or HER2 activation.31 GSK-2016 is a dual inhibitor of EGFR and HER2, which, unlike CI-1033, causes reversible inhibition.32 Preclinical studies of GSK in combination with radiotherapy are underway. Another approach to HER inhibition has been to use a dominant negative EGFR construct consisting on the extracellular domain of the EGFR with the cytoplasmic domain deleted. The resulting construct, CD-533, is able to bind ligand and dimerize with wild-type EGFR or other EGFR family members but unable to phosphorylate itself or the dimeric partner and thus unable to activate signal transduction cascades. Inducible expression of this construct inhibits radiation-induced EGFR activation and resumption of proliferation after fractionated radiation (5 fractions of 2 Gy), but not clonogenic survival after single-dose radiation.33 Expression of CD-533 in human breast cancer xenografts using an adenoviral system increased response to a 3-day course of radiation at 1.5 Gy/d, with a dose-enhancement ratio of 1.85.34 Similarly, a cytoplasmic deletion mutant of the neu oncogene (the oncogenic homologue of HER2, containing an activating mutation in the transmembrane domain) sensitized radioresistant glioma cells.35 Clinical studies of HER inhibitors as radiosensitizers The clinical development of C225, Herceptin, and Iressa are well underway, and early phase trials are ongoing or recently completed with CI-1033, GSK-2016, and other kinase inhibitors.4 Although clinical investigations have primarily focused on use of inhibitors alone or in combination with chemotherapy, some studies have explored the feasibility and efficacy of using these inhibitors as radiosensitizers. The initial results of a trial of C225 plus radiotherapy in patients with locally advanced head and neck cancer were reported at the American Society of Clinical Oncology meeting in 2000. With 15 evaluable patients, the complete response rate was 87%, with a median duration of response of 13.9 months.36 A phase II trial of patients with locally advanced or recurrent head and neck cancer of C225 plus cisplatin and concomitant radiotherapy has completed accrual, and encouraging results supported the initiation of a phase III trial (UAB-9901) to determine the efficacy of C225 plus radiotherapy in patients with locally advanced head and neck cancer (Fig 2).
Patients are randomized to receive weekly C225 or not while undergoing radiotherapy with either concurrent boost, daily, or twice daily radiotherapy regimens. Planned accrual is 416 patients over 5 years. The endpoints are rates of local control at 1 year with and without C225, response rates, progression-free survival, and overall survival, along with toxicity and quality of life evaluations. Iressa is being investigated in the lung cancer setting in combination with chemotherapy or after chemoradiotherapy.37 However, the radiosensitizing potential of Iressa is being explored in patients with head and neck cancer. A phase I study of Iressa and radiotherapy with or without cisplatin in patients with locally advanced disease has been approved (UCHSC-01460). Patients receive Iressa daily 2 weeks before and throughout radiotherapy. Radiotherapy (RT) is initially delivered using concurrent boost fractionation with escalating dose Iressa, then cisplatin is delivered with daily RT over 7 weeks with escalating dose of Iressa, and, finally, RT using concurrent boost is given with cisplatin and Iressa if tolerated (Fig 3).
The primary objectives are to determine the maximum tolerated dose of Iressa in combination with radiotherapy with or without cisplatin, as well as to determine the feasibility and toxicity profile of protracted continuous daily Iressa after definitive radiotherapy. Although HER2 overexpressing tumors constitute a relatively small proportion of malignancies, Herceptin is an attractive potential radiosensitizer because preclinical studies using breast epithelial cell lines indicate that it may spare normal tissues from sensitization (Sartor, unpublished data). Two trials are investigating the radiosensitizing potential of Herceptin. A phase I/II trial underway at the University of North Carolina and University of Colorado (LCCC9925) seeks to determine the acute toxicity of concurrent Herceptin and radiotherapy, as well as response rate of locally advanced breast cancer to primary radiation and Herceptin (Fig 4).
Patients who are considered candidates for primary RT (eg, inflammatory breast cancer) are treated with concurrent Herceptin and radiotherapy at standard dose and fractionation followed by surgery. Pathologic complete response rate is the primary efficacy endpoint. A dose-escalation trial of Herceptin delivered with chemoradiotherapy for adenocarcinoma of the esophagus is underway at Brown University, Providence, RI. Patients with T3 or T4 disease receive weekly paclitaxel, cisplatin, and Herceptin during a course of 50 Gy delivered in 28 fractions over 6 weeks. The Herceptin dose is escalated from 1 mg/kg/wk to 2 mg/kg/wk, which is the standard dose. In addition, several ongoing phase III clinical trials designed to test the efficacy of Herceptin when combined with chemotherapy in patients with locally advanced breast cancer deliver Herceptin concurrent with radiotherapy (NCCTG 9831 and NSABP B-31). Although these trials are not designed to determine whether Herceptin is improving radiotherapy response, they will gather substantial data regarding potential cardiotoxicity. Herceptin alone causes a slight risk of cardiac dysfunction, and addition of doxorubicin has been shown to significantly increase the risk of clinical or subclinical congestive heart failure in the acute and subacute setting.38 Although laboratory results suggest that radiosensitization is limited to HER2 overexpressing cells, long-term toxicity is not evaluable in the studies performed to date. Thus, whether Herceptin will exacerbate the risk of radiation-induced cardiotoxicity is unknown; it is a highly relevant question because cardiac toxicity must be minimized to realize a benefit from adjuvant radiation in some clinical settings.39 At present, the mechanism of increased cardiac toxicity of Herceptin plus doxorubicin remains unclear but may be because of a requirement for HER2 during repair of cardiac damage, suggested by studies that show that HER2 is upregulated in response to cardiac stress.40 Potential mechanisms of radiosensitization by HER inhibitors The most appropriate use of HER inhibitors as radiosensitizers depends on a thorough understanding of the underlying mechanisms of radioresistance because of HER activation and radiosensitization by inhibitors. There are several potential mechanisms identified thus far, and these diverse effects likely overlap in complex interactions. One way in which dysregulation of the receptors may promote radioresistance is by disrupting the balance of downstream signal transduction pathways to favor survival signals (Fig 5).
p44/42 MAPK (erks) are primarily involved in transmitting proliferative signals, whereas JNK and p38 are involved in stress-response signals. 41 The balance between MAPK and JNK has been implicated in apoptosis versus survival responses to ionizing radiation and other stress stimuli. 42 In some contexts, JNK promotes apoptosis after IR, whereas MAPK provides survival signals that oppose the JNK-activated prodeath signals. 43, 44 IR-induced activation of EGFR is followed by activation of MAPK. 15 Inhibition of IR-induced MAPK activation by a MAPK inhibitor increases acute activation of JNK, suggesting that MAPK signals exert a negative regulatory effect on JNK. 45 The increase in JNK activation with MAPK inhibition is associated with modest but statistically significant increase in apoptosis and growth arrest in response to fractionated radiation. Expression of CD-533, the dominant negative EGFR construct, inhibits EGFR activation and acute MAPK activation but not acute JNK activation and also modestly increases apoptosis and growth arrest in response to IR. Thus, alteration of the balance between a MAPK progrowth signal and JNK proapoptotic signal by EGFR activation after IR may result in radioresistance, whereas inhibition of EGFR signal by a dominant negative construct, or, more specifically, inhibition of MAPK by a MAPK inhibitor alters the JNK-MAPK balance after IR to favor proapoptotic and antiproliferative signals. However, the temporal relationship and duration of signaling by these signal transduction pathways may be critical because later JNK activation induced by IR was not affect by either inhibitor. Similarly, in the radiation-refractory breast cancer sublines that express constitutive activation of EGFR, MAPK activation was increased whereas JNK activation suppressed in response to EGF stimulation, suggesting that alteration of the JNK-MAPK axis may be related to the survival and repopulation of cells after fractionated IR. 17Aberrant activation of the PI3K-Akt signal transduction pathway, another pathway through which HERs signal, correlates with radioresistance in both head and neck and lung cancer. Sixteen of 17 non–small-cell lung cancer lines were found to have constitutively active Akt, and pharmacologic inhibition of PI3K/Akt increased radiation-induced apoptosis and reduced clonogenic survival.46 Transient transfection of Akt recapitulated the phenotype in cell lines without constitutive Akt. In head and neck tumors, phosphorylated (active) Akt correlates with local recurrence after IR.6 Inhibition of the PI3K-Akt pathway in a radioresistant H&N cancer cell line sensitized to IR. PI3K-Akt signaling has been shown to be at least partially responsible for Ras-mediated radioresistance.6, 47 In some situations, EGFR may be involved in Ras-mediated radioresistance because cells expressing activated Ras release factors into the medium that activate EGFR and enhance clonogenic survival after IR.48 NF-κB, a transcription factor downstream from PI3K-Akt has also been implicated in enhancing survival after IR.49 HER2 overexpression is associated with constitutive activation of NF-κB.50, 51 HER inhibitors may increase radiosensitization by blocking these or other survival pathways downstream from EGFR, as evidenced by enhanced radiation-induced apoptosis with C225.25, 52 In addition to the potential of HER inhibitors to reverse prosurvival signals emanating from EGFR family members, they may also sensitize cells to IR by altering cell cycle control. Several of the inhibitors have been shown to induce G0/G1 arrest and reduce S phase when used alone, and this alteration in cell cycle distribution redistributes cells from relatively resistant phases of the cell cycle (S phase) to more sensitive phases. Cell cycle alterations resulting from C225 correlated with increase radiation-induced apoptosis.25, 52 Herceptin also reduces the percentage of cells in S phase, but after radiation in the presence of Herceptin, cells re-enter the cell cycle more rapidly, suggesting that Herceptin may be interfering with IR-induced arrest.20 HER inhibitors also affect repair processes, another potential mechanism of radiation-response modulation. Herceptin decreases unscheduled DNA repair after radiation.20 Potentially lethal damage repair is inhibited by C225, suggesting that radiosensitization may be enhanced when C225 is used in the clinical setting of fractionated radiotherapy.53 C225 induces a physical interaction between EGFR and DNA-PK in the cytosol, perhaps preventing access of DNA-PK to the nucleus.52 HER inhibitors may also affect radioprotective mechanisms because glutathione levels are reduced in C225-treated MCF7 cells.10 Finally, HER inhibitors affect angiogenesis. EGFR activation upregulates VEGF production and EGFR inhibitors have significant effects on tumor angiognesis. C225 reduces VEGF expression, potentially sensitizing tumor endothelial cells to radiation-induced damage.54 Like C225, inhibition with Iressa decreased VEGF expression in tumors and reduced angiogenesis.55 In A431 xenografts, C225 combined with IR significantly enhanced necrosis, accompanied by disruption of tumor vascularity and reduced angiogenesis.53 These effects on tumor-stroma interactions may explain the greater sensitization seen in vivo even when only modest effects are seen using in vitro assays. Conclusions and future directions EGFR and HER2 have been directly and indirectly implicated in radiation response, and inhibition with blocking antibodies or with kinase inhibitors shows promise in preclinical and clinical trials. The mechanisms of radioresistance and radiosensitization appear complex and diverse, including effects on survival signals, cell cycle regulation, DNA repair, and angiogenesis. Tumors may exploit any of many mechanisms of radioresistance, and the challenge will be to identify the appropriate inhibitor for a particular tumor. In addition, exploration of mechanisms of sensitization by HER inhibitors will help to identify key targets that may be used as biological endpoints to gauge effective sensitization, a development that will greatly facilitate investigation of appropriate tumor selection, sequencing of modalities, and optimal dose of inhibitor for radiosensitization, and potential combined therapy with other biological modifiers for enhanced sensitization. References 1.
1
Yarden Y.
The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities.
Eur J Cancer. 2001;4(suppl):S3–S8. 2.
2
Baselga J.
The EGFR as a target for anticancer therapy—Focus on cetuximab.
Eur J Cancer. 2001;4(suppl):S16–S22. 3.
3
Klapper LN, Waterman H, Sela M, et al.
Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cb1 and enhancing ubiquitination of HER-2.
Cancer Res. 2000;60:3384–3388. MEDLINE 4.
4
Ciardiello F, Tortora G.
A novel approach in the treatment of cancer: Targeting the epidermal growth factor receptor.
Clin Cancer Res. 2001;7:2958–2970. MEDLINE 5.
5
Barker FG, Simmons ML, Chang SM, et al.
EGFR overexpression and radiation response in glioblastoma multiforme.
Int J Radiat Oncol Biol Phys. 2001;51:410–418. Abstract | Full Text |
Full-Text PDF (936 KB)
|
CrossRef
6.
6
Gupta AK, McKenna WG, Weber CN, et al.
Local recurrence in head and neck cancer: Relationship to radiation resistance and signal transduction.
Clin Cancer Res. 2002;8:885–892. MEDLINE 7.
7
Sheridan MT, O'Dwyer T, Seymour CB, et al.
Potential indicators of radiosensitivity in squamous cell carcinoma of the head and neck.
Radiat Oncol Investig. 1997;5:180–186. MEDLINE |
CrossRef
8.
8
FitzGerald TJ, Henault S, Sakakeeny M, et al.
Expression of transfected recombinant oncogenes increases radiation resistance of clonal hematopoietic and fibroblast cell lines selectively at clinical low dose rate.
Radiat Res. 1990;122:44–52. MEDLINE |
CrossRef
9.
9
Balaban N, Moni J, Shannon M, et al.
The effect of ionizing radiation on signal transduction: Antibodies to EGF receptor sensitize A431 cells to radiation.
Biochim Biophys Acta. 1996;1314:147–156. MEDLINE 10.
10
Wollman R, Yahalom J, Maxy R, et al.
Effect of epidermal growth factor on the growth and radiation sensitivity of human breast cancer cells in vitro.
Int J Radiat Oncol Biol Phys. 1994;30:91–98. MEDLINE 11.
11
Kwok TT, Sutherland RM.
Differences in EGF related radiosensitisation of human squamous carcinoma cells with high and low numbers of EGF receptors.
Br J Cancer. 1991;64:251–254. MEDLINE 12.
12
Bonner JA, Maihle NJ, Folven BR, et al.
The interaction of epidermal growth factor and radiation in human head and neck squamous cell carcinoma cell lines with vastly different radiosensitivities.
Int J Radiat Oncol Biol Phys. 1994;29:243–247. MEDLINE |
CrossRef
13.
13
Schmidt-Ullrich RK, Mikkelsen RB, Dent P, et al.
Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation.
Oncogene. 1997;15:1191–1197. MEDLINE 14.
14
Todd DG, Mikkelsen RB, Rorrer WK, et al.
Ionizing radiation stimulates existing signal transduction pathways involving the activation of epidermal growth factor receptor and ERBB- 3, and changes of intracellular calcium in A431 human squamous carcinoma cells.
J Recept Signal Transduct Res. 1999;19:885–908. MEDLINE |
CrossRef
15.
15
Carter S, Auer KL, Reardon DB, et al.
Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells.
Oncogene. 1998;16:2787–2796. MEDLINE 16.
16
Schmidt-Ullrich RK, Valerie KC, Chan W, et al.
Altered expression of epidermal growth factor receptor and estrogen receptor in MCF-7 cells after single and repeated radiation exposures.
Int J Radiat Oncol Biol Phys. 1994;29:813–819. Abstract |
Full-Text PDF (897 KB)
|
CrossRef
17.
17
Zhou H, Dy R, Sartor C.
A New Series of Radioresistant Breast Cancer Cell Lines Demonstrate Frequent Alterations in EGFR Signaling.
Ventura, CA: Gordon Research Conference,; January 28-February 2, 2001;. 18.
18
Haffty BG, Brown F, Carter D, et al.
Evaluation of HER-2 neu oncoprotein expression as a prognostic indicator of local recurrence in conservatively treated breast cancer: A case-control study.
Int J Radiat Oncol Biol Phys. 1996;35:751–757.
Full-Text PDF (3211 KB)
|
CrossRef
19.
19
Pirollo KF, Tong YA, Villegas Z, et al.
Oncogene-transformed NIH 3T3 cells display radiation resistance levels indicative of a signal transduction pathway leading to the radiation- resistant phenotype.
Radiat Res. 1993;135:234–243. MEDLINE |
CrossRef
20.
20
Pietras RJ, Poen JC, Gallardo D, et al.
Monoclonal antibody to HER-2/neureceptor modulates repair of radiation- induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene.
Cancer Res. 2001;59:1347–1355. MEDLINE 21.
21
Harari PM, Huang SM.
Radiation response modification following molecular inhibition of epidermal growth factor receptor signaling.
Semin Radiat Oncol. 2001;11:281–289. Abstract |
Full-Text PDF (2400 KB)
|
CrossRef
22.
22
Harari PM, Huang SM.
Head and neck cancer as a clinical model for molecular targeting of therapy: Combining EGFR blockade with radiation.
Int J Radiat Oncol Biol Phys. 2001;49:427–433. Abstract | Full Text |
Full-Text PDF (868 KB)
|
CrossRef
23.
23
Nasu S, Ang KK, Fan Z, et al.
C225 antiepidermal growth factor receptor antibody enhances tumor radiocurability.
Int J Radiat Oncol Biol Phys. 2001;51:474–477. Abstract | Full Text |
Full-Text PDF (67 KB)
|
CrossRef
24.
24
Raben D, Buchsbaum D, Gillespie Y, et al.
Treatment of human intracranial gliomas with chimeric monoclonal antibody against the epidermal growth factor receptor increases survival of nude mice when treated concurrently with irradiation.
In: American Association for Cancer Research 90th Annual Meeting A1224. Philadelphia, PA: Cancer Research; 1999;. 25.
25
Helfrich B, Phistry M, Chan D, et al.
ZD1839 (Iressa), a Selective EGFR-TKI, Enhances Radiation and Chemotherapy Cytotoxicity in EGFR Positive Human Non-Small Cell Lung Cancer Cells (NSCLC) in Vitro.
In: Molecular Biology and New Treatment Strategies: Cancer Research in the 21st Century, Maui, HI,. 2001;p. B10. 26.
26
Williams K, Telfer B, Stratford I, et al.
Combination of ZD1839 (Iressa), and EGFR-TKI, and radiotherapy increases antitumor efficacy in a human colon cancer xenograft.
In: American Association for Cancer Research 92nd Annual Meeting, New Orleans, LA, Cancer Research, A3480. 2001;. 27.
27
She Y, Lee F, Haimovitz-Friedman A, et al.
The selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) enhances radiation sensitivity of human tumor xenografts in nude mice.
In: American Association for Cancer Research 93rd Annual Meeting, San Francisco, CA, Cancer Research, A3894,. 2002;. 28.
28
Stea B, Falsey R, Carey S, et al.
Growth inhibition and radiosensitization of glioblastoma multiforme by the tyrosine kinase inhibitor ZD1839 (Iressa).
In: American Association for Cancer Research 93rd Annual Meeting, San Francisco, CA, Cancer Research, A3899,. 2002;. 29.
29
Anido J, Albanell J, Rojo F, et al.
ZD1839 (Iressa), a specific epidermal growth factor receptor tyrosine kinase inhibitor, induces the formatin of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2 overexpressing breast cancer cells.
In: American Association for Cancer Research 93rd Annual Meeting, San Francisco, CA, Cancer Research, A3881,. 2002;. 30.
30
Christensen JG, Schreck RE, Chan E, et al.
High levels of HER-2 expression alter the ability of epidermal growth factor receptor (EGFR) family tyrosine kinase inhibitors to inhibit EGFR phosphorylation in vivo.
Clin Cancer Res. 2001;7:4230–4238. MEDLINE 31.
31
Rao GS, Murray S, Ethier SP.
Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor.
Int J Radiat Oncol Biol Phys. 2000;48:1519–1528. Abstract | Full Text |
Full-Text PDF (454 KB)
|
CrossRef
32.
32
Rusnak DW, Affleck K, Cockerill SG, et al.
The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.
Cancer Res. 2001;61:7196–7203. MEDLINE 33.
33
Contessa JN, Reardon DB, Todd D, et al.
The inducible expression of dominant-negative epidermal growth factor receptor-CD533 results in radiosensitization of human mammary carcinoma cells.
Clin Cancer Res. 1999;5:405–411. MEDLINE 34.
34
Lammering G, Hewit TH, Hawkins WT, et al.
Epidermal growth factor receptor as a genetic therapy target for carcinoma cell radiosensitization.
J Natl Cancer Inst. 2001;93:921–929. MEDLINE 35.
35
O'Rourke DM, Kao GD, Singh N, et al.
Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells.
P Natl Acad Sci. 1998;95:10842–10847. 36.
36
Bonner J, Ezekiel M, Robert F, et al.
Continued response following treatment with IMC-C225, and EGFr MoAb combined with RT in advanced head and neck malignancies.
In: American Society of Clinical Oncology 36th Annual Meeting 5F. New Orleans, LA: Journal of Clinical Oncology; 2000;. 37.
37
Raben D, Helfrich BA, Chan D, et al.
ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer.
Semin Oncol. 2002;29:37–46. Abstract | Full Text |
Full-Text PDF (107 KB)
|
CrossRef
38.
38
Seidman A, Hudis C, Pierri MK, et al.
Cardiac dysfunction in the trastuzumab clinical trials experience.
J Clin Oncol. 2002;20:1215–1221.
CrossRef
39.
39
Early Breast Cancer Trialists' Collaborative Group .
Favourable and unfavorable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials.
Lancet. 2000;355:1757–1770. Abstract | Full Text |
Full-Text PDF (376 KB)
|
CrossRef
40.
40
Rohrbach S, Yan X, Weinberg EO, et al.
Neuregulin in cardiac hypertrophy in rats with aortic stenosis. Differential expression of erbB2 and erbB4 receptors.
Circulation. 1999;100:407–412. 41.
41
Davis RJ.
Signal transduction by the JNK group of MAP kinases.
Cell. 2000;103:239–252. MEDLINE |
CrossRef
42.
42
Canman CE, Kastan MB.
Signal transduction. Three paths to stress relief.
Nature. 1996;384:213–214. MEDLINE |
CrossRef
43.
43
Verheij M, Bose R, Lin XH, et al.
Requirement for ceramide-initiated SAPK/JNK signalling in stress- induced apoptosis.
Nature. 1996;380:75–79. MEDLINE |
CrossRef
44.
44
Ruiter GA, Zerp SF, Bartelink H, et al.
Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis.
Cancer Res. 1999;59:2457–2463. MEDLINE 45.
45
Reardon DB, Contessa JN, Mikkelsen RB, et al.
Dominant negative EGFR-CD533 and inhibition of MAPK modify JNK1 activation and enhance radiation toxicity of human mammary carcinoma cells.
Oncogene. 1999;18:4756–4766. MEDLINE |
CrossRef
46.
46
Brognard J, Clark AS, Ni Y, et al.
Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation.
Cancer Res. 2001;61:3986–3997. MEDLINE 47.
47
Grana T, Rusyn E, Zhou H, et al.
Ras mediates radioresistance through both PI3-K-dependent and Raf-dependent but MEK-independent signaling pathways.
Cancer Res. 2002;62:4142–4150. MEDLINE 48.
48
Grana T, Zhou H, Sartor C, et al.
Ras-mediated radiation resistance via autocrine pathways.
In: Radiation Research Society 49th Annual Meeting, Reno, NV,. 2002;p. P29–P288. 49.
49
Baldwin AS.
Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB.
J Clin Invest. 2001;107:241–246. MEDLINE |
CrossRef
50.
50
Pianetti S, Arsura M, Romieu-Mourez R, et al.
Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN.
Oncogene. 2001;20:1287–1299. MEDLINE |
CrossRef
51.
51
Zhou BP, Hu MC, Miller SA, et al.
HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway.
J Biol Chem. 2000;275:8027–8031. MEDLINE |
CrossRef
52.
52
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. 1999;59:1935–1940. MEDLINE 53.
53
Milas L, Mason K, Hunter N, et al.
In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody.
Clin Cancer Res. 2000;6:701–708. MEDLINE 54.
54
Huang SM, Harari PM.
Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: Inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis.
Clin Cancer Res. 2000;6:2166–2174. MEDLINE 55.
55
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. 2001;7:1459–1465. MEDLINE Department of Radiation Oncology and UNC/Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC. ☆ Supported in part by 1-K08-CA83753, National Institutes of Health. ☆☆ Address reprint requests to Carolyn I. Sartor, MD, UNC Hospitals, Department of Radiation Oncology, NC Clinical Cancer Center, 101 Manning Drive, Chapel Hill, NC 27514. PII: S1053-4296(03)50005-4 doi:10.1053/srao.2003.50003 © 2003 Published by Elsevier Inc. | |
|
FULL TEXT50005-4/journalimage?img=PIIS1053429603500054.gr1.lrg.gif&fig=fig1&kwhquery=&issn=1053-4296&ishighres=false&allhighres=false&free=yes','journalimage');)
50005-4/journalimage?img=PIIS1053429603500054.gr2.lrg.gif&fig=&kwhquery=&issn=1053-4296&ishighres=false&allhighres=false&free=yes','journalimage');)
50005-4/journalimage?img=PIIS1053429603500054.gr3.lrg.gif&fig=&kwhquery=&issn=1053-4296&ishighres=false&allhighres=false&free=yes','journalimage');)
50005-4/journalimage?img=PIIS1053429603500054.gr4.lrg.gif&fig=&kwhquery=&issn=1053-4296&ishighres=false&allhighres=false&free=yes','journalimage');)
50005-4/journalimage?img=PIIS1053429603500054.gr5.lrg.gif&fig=&kwhquery=&issn=1053-4296&ishighres=false&allhighres=false&free=yes','journalimage');)