ABSTRACT Cellular heterogeneity, redundancy of molecular pathways and effects of the microenvironment contribute to the survival, motility and metastasis of cells in solid tumors. It is

unlikely that tumors are entirely dependent on only one abnormally activated signaling pathway; consequently, treatment with an agent that interferes with a single target may be

insufficient. Combined blockade of functionally linked and relevant multiple targets has become an attractive therapeutic strategy. The EGFR and ERBB2 (HER2) pathways and VEGF-dependent

angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and has demonstrated a suggested

against VEGF and ERBB respectively, or, alternatively, a single multitargeted agent, can be used. Preclinical studies have proven the efficacy of both these approaches and early clinical

studies have provided encouraging results. This Review discusses the experimental rationale for, preclinical studies of and clinical trials on combined blockade of ERBB and VEGF signaling.

KEY POINTS * The heterogeneity of tumors and the wide degree of crosstalk among different signaling pathways compel a therapeutic approach directed against multiple complementary targets *

EGFR, ERBB2 and VEGF have close functional interactions, control tumor and endothelial cell compartments, and are involved directly in the mechanisms of resistance to current therapies *

Combined targeting of ERBB receptors and VEGF-dependent signaling has proven to be a successful strategy in preclinical studies and has been translated to the clinical setting * There are

two main strategies pursued in preclinical and clinical studies—the first is based on the combination of two selective agents, including monoclonal antibodies and small-molecule tyrosine

kinase inhibitors that target ERBB and VEGF, and the second on single multitargeted small-molecule inhibitors that simultaneously block VEGF receptors and ERBB * Both approaches have been

used in early clinical studies in different types of cancer, and activity has been obtained in different tumors, especially in non-small-cell lung cancer * The safety profile of

multitargeted agents is generally good, and adverse effects seem to occur by the addition of chemotherapeutic regimens Access through your institution Buy or subscribe This is a preview of

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THERAPEUTIC TARGETING OF EPHA2 IN CANCER Article 08 March 2021 WHEN THE MET RECEPTOR KICKS IN TO RESIST TARGETED THERAPIES Article 24 May 2021 NEUTRALIZATION OF THE INDUCED VEGF-A

POTENTIATES THE THERAPEUTIC EFFECT OF AN ANTI-VEGFR2 ANTIBODY ON GASTRIC CANCER IN VIVO Article Open access 23 July 2021 REFERENCES * Citri A and Yarden Y (2006) EGF-ERBB signalling: towards

the systems level. _Nat Rev Mol Cell Biol_ 7: 505–516 Article  CAS  Google Scholar  * Hynes NE and Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. _Nat Rev

Cancer_ 5: 341–354 Article  CAS  Google Scholar  * Mendelsohn J and Baselga J (2006) Epidermal growth factor receptor targeting in cancer. _Semin Oncol_ 33: 369–385 Article  CAS  Google

Scholar  * Normanno N _ et al_. (2003) Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. _Endocr Relat Cancer_ 10: 1–21 Article  CAS  Google

Scholar  * Baselga J and Arteaga CL (2005) Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. _J Clin Oncol_ 23: 2445–2459 Article  CAS  Google

Scholar  * Hanahan D and Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. _Cell_ 86: 353–364 Article  CAS  Google Scholar  * Folkman J (1971)

Tumor angiogenesis: therapeutic implications. _N Engl J Med_ 285: 1182–1186 Article  CAS  Google Scholar  * Ferrara N _ et al_. (2003) The biology of VEGF and its receptors. _Nat Med_ 9:

669–676 Article  CAS  Google Scholar  * Fox SB _ et al_. (2001) Angiogenesis: pathological, prognostic, and growth factor pathways and their link to trial design and anticancer drugs.

_Lancet Oncol_ 2: 278–289 Article  CAS  Google Scholar  * Kerbel R and Folkman J (2002) Clinical translation of angiogenesis inhibitors. _Nat Rev Cancer_ 2: 727–739 Article  CAS  Google

Scholar  * Patiar S and Harris AL (2006) Role of hypoxia-inducible factor-1alpha as a cancer therapy target. _Endocr Relat Cancer_ 13 (Suppl 1): S61–S75 Article  CAS  Google Scholar  *

Shibuya M (2006) Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. _J Biochem Mol Biol_ 39: 469–478 CAS  PubMed  Google Scholar  * Ellis L

(2004) Epidermal growth factor receptor in tumor angiogenesis. _Hematol Oncol Clin North Am_ 18: 1007–1021 Article  Google Scholar  * Fan F _ et al_. (2005) Expression and function of

vascular endothelial growth factor receptor-1 on human colorectal cancer cells. _Oncogene_ 24: 2647–2653 Article  CAS  Google Scholar  * Gasparini G and Harris AL (1995) Clinical implication

of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool. _J Clin Oncol_ 13: 765–782 Article  CAS  Google Scholar  * Fontanini G _ et al_. (1997)

Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. _Clin Cancer Res_ 3: 861–865 CAS  PubMed  Google

Scholar  * Gasparini G _ et al_. (2005) Angiogenic inhibitors: a new therapeutic strategy in oncology. _Nat Clin Pract Oncol_ 2: 562–577 Article  CAS  Google Scholar  * Gasparini G _ et al_.

(2005) Combination of angiogenic therapy with other anticancer therapies: results, challenges and open questions. _J Clin Oncol_ 20: 1275–1311 Google Scholar  * Kim SJ _ et al_. (2003)

Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of

nude mice. _Clin Cancer Res_ 9: 1200–1210 CAS  PubMed  Google Scholar  * Okamura _ et al_. (1992) A model system for tumour angiogenesis: involvement of transforming growth factor-a in tube

formation of human microvascular endothelial cells induced by esophageal cancer cells. _Biochem Biophys Res Commun_ 186: 1471–1479 Article  CAS  Google Scholar  * Hirata A _ et al_. (2002)

ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. _Cancer Res_ 62: 2554–2560 CAS  Google Scholar  * Goldman CK _ et al_.

(1993) Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. _Mol Biol Cell_

4: 121–133 Article  CAS  Google Scholar  * Parikh AA _ et al_. (2003) Expression and regulation of the novel vascular endothelial growth factor receptor neuropilin-1 by epidermal growth

factor in human pancreatic carcinoma. _Cancer_ 98: 720–729 Article  CAS  Google Scholar  * Turini ME and DuBois RN (2002) Cyclooxygenase-2: a therapeutic target. _Annu Rev Med_ 53: 35–57

Article  CAS  Google Scholar  * Caputo R _ et al_. (2003) Helicobacter pylori VacA toxin up-regulates vascular endothelial growth factor expression in MKN 28 gastric cells through an

epidermal growth factor receptor-, cyclooxygenase-2-dependent mechanism. _Clin Cancer Res_ 9: 2015–2021 CAS  PubMed  Google Scholar  * Loureiro RM (2005) ErbB2 overexpression in mammary

cells upregulates VEGF through the core promoter. _Biochem Biophys Res Comm_ 326: 455–465 Article  CAS  Google Scholar  * Wen XF _ et al_. (2006) HER2 signaling modulates the equilibrium

between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. _Oncogene_ 25: 6986–6996 Article  CAS  Google Scholar  * Phillips RJ _ et al_.

(2005) Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/

mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1α. _J Biol Chem_ 280: 22473–22481 Article  CAS  Google Scholar  * Laughner E _ et al_. (2001) HER2

(neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. _Mol Cell Biol_ 21:

3995–4004 Article  CAS  Google Scholar  * Izumi Y _ et al_. (2002) Tumour biology: herceptin acts as an anti-angiogenic cocktail. _Nature_ 416: 279–280 Article  CAS  Google Scholar  *

Tabernero J (2007) The role of VEGF and EGFR inhibition: implications for combining anti–VEGF and anti–EGFR agents. _Mol Cancer Res_ 5: 203–220 Article  CAS  Google Scholar  * Petit AM _ et

al_. (1997) Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumour cells in

vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumours. _Am J Pathol_ 151: 1523–1530 CAS  PubMed  PubMed Central  Google Scholar  * Bruns CJ _ et al_.

(2000) Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic

mechanisms. _Clin Cancer Res_ 6: 1936–1948 CAS  PubMed  Google Scholar  * Ciardiello F _ et al_. (2001) 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 CAS  Google Scholar  * Bruns CJ _ et al_. (2000) Blockade of the

epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. _Cancer Res_ 60: 2926–2935

CAS  PubMed  Google Scholar  * Perrotte P _ et al_. (1999) 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 CAS  PubMed  Google Scholar  * Kedar D _ et al_. (2002) Blockade of the epidermal growth factor receptor signaling inhibits

angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice. _Clin Cancer Res_ 8: 592–600 Google Scholar  * Viloria-Petit A _ et al_. (2001) Acquired

resistance to the antitumor effect of epidermal growth factor receptor–blocking antibodies in vivo: a role for altered tumor angiogenesis. _Cancer Res_ 61: 5090–5101 CAS  PubMed  Google

Scholar  * Ciardiello F _ et al_. (2004) Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine inhibitor, in human cancer cells with acquired resistance to

anti-epidermal growth factor therapy. _Clin Cancer Res_ 10: 784–793 Article  CAS  Google Scholar  * Vallbohmer D _ et al_. (2005) Molecular determinants of cetuximab efficacy. _J Clin Oncol_

23: 3536–3544 Article  Google Scholar  * Ciardiello F _ et al_. (1996) Antitumor activity of combined blockade of epidermal growth factor receptor and protein kinase A. _J Natl Cancer Inst_

88: 1770–1776 Article  CAS  Google Scholar  * Ciardiello F _ et al_. (2000) Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in

combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. _Clin Cancer Res_ 6: 3739–3747 CAS  Google Scholar  * Shaheen RM _ et al_.

(2001) Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. _Br J Cancer_ 85: 584–589 Article  CAS  Google Scholar  *

Jung YD _ et al_. (2002) Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude

mouse model. _Eur J Cancer_ 38: 1133–1140 Article  CAS  Google Scholar  * Ryan AJ and Wedge SR (2005) ZD6474 a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. _Br J Cancer_ 92

(Suppl 1): S6–S13 Article  CAS  Google Scholar  * McCarty MF _ et al_. (2004) ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against

epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer. _Mol Cancer Ther_ 3: 1041–1048 CAS  PubMed  Google Scholar  * Drevs J _ et

al_. (2004) The VEGF receptor tyrosine kinase inhibitor, ZD6474, inhibits angiogenesis and affects microvascular architecture within an orthotopically implanted renal cell carcinoma.

_Angiogenesis_ 7: 347–354 Article  CAS  Google Scholar  * Yokoi K _ et al_. (2005) Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor

phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. _Cancer Res_ 65: 3716–3725 Article  CAS  Google Scholar  * Park YW _ et

al_. (2005) AEE788, a dual tyrosine kinase receptor inhibitor, induces endothelial cell apoptosis in human cutaneous squamous cell carcinoma xenografts in nude mice. _Clin Cancer Res_ 11:

1963–1973 Article  CAS  Google Scholar  * Dickler M _ et al_. (2004) Phase II trial of erlotinib (OSI-774), an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, and

bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF), in patients (pts) with metastatic breast cancer (MBC). _J Clin Oncol_ 22 (Suppl): 127s

Google Scholar  * Pegram M . _ et al_. (2006) Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and

bevacizumab (B) as first line treatment of HER2-amplified breast cancer [abstract #301]. Presented at the 29th Annual San Antonio Breast Cancer Symposium December 14–17 2006, San Antonio,

TX, USA. * Sarmiento R _ et al_. (2007) Preliminary results of a dose-finding study of PTK787/ZK222584 (PTK/ZK) in combination with weekly vinorelbine (V) and trastuzumab (T) as treatment of

patients (pts) with metastatic breast cancer (MBC) overexpressing HER-2/neu, previously treated with at least one line of chemotherapy (CT) [abstract #40247]. Presented at the American

Society of Clinical Oncology Breast Cancer Symposium * Saltz LB _ et al_. (2007) Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab

alone in irinotecan–refractory colorectal cancer: the BOND-2 study. _J Clin Oncol_ 25: 4557–4561 Article  CAS  Google Scholar  * Zhu Z (2007) Targeted cancer therapies based on antibodies

directed against epidermal growth factor receptor: status and perspectives. _Acta Pharmacol Sin_ 28: 1476–1493 Article  CAS  Google Scholar  * Meyerhardt JA _ et al_. (2007) Phase II study

of FOLFOX, bevacizumab and erlotinib as first-line therapy for patients with metastatic colorectal cancer. _Ann Oncol_ 18: 1185–1189 Article  CAS  Google Scholar  * Herbst RS _ et al_.

(2005) Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase

inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. _J Clin Oncol_ 23: 2544–2555 Article  CAS  Google Scholar  * Herbst RS _ et al_. (2007) Phase II study of efficacy

and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. _J Clin Oncol_

25: 4743–4750 Article  CAS  Google Scholar  * Natale RB _ et al_. (2006) ZD6474 versus gefitinib in patients with advanced NSCLC: final results from a two-part, double-blind, randomized

phase II trial. _J Clin Oncol_ 24 (Suppl): 364s Google Scholar  * Heymach JV _ et al_. (2004) ZD6474, a novel antiangiogenic agent, in combination with docetaxel in patients with NSCLC:

results of the run-in phase of a two-part, randomised phase II study. _J Clin Oncol_ 22 (Suppl): 207s Google Scholar  * Heymach JV _ et al_. (2007) Randomized, placebo-controlled phase II

study of vandetanib plus docetaxel in previously treated non small-cell lung cancer. _J Clin Oncol_ 25: 4270–4277 Article  CAS  Google Scholar  * Hainsworth JD _ et al_. (2005) Treatment of

metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. _J Clin Oncol_ 23: 7889–7896 Article  CAS  Google Scholar  * Bukowski RM _ et al_. (2007) Randomized phase II

study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. _J Clin Oncol_ 25: 4536–4541 Article  CAS  Google Scholar  * Mauer AM _ et al_.

(2004) Phase I study of epidermal growth factor receptor (EGFR) inhibitor, erlotinib, and vascular endothelial growth factor monoclonal antibody, bevacizumab, in recurrent and/or metastatic

squamous cell carcinoma of the head and neck (SCCHN). _J Clin Oncol_ 22 (Suppl): 497s Google Scholar  * Vokes EE _ et al_. (2006) A phase I study of erlotinib and bevacizumab for recurrent

or metastatic squamous cell carcinoma of the head and neck (HNC). _J Clin Oncol_ 23 (Suppl): 501s Google Scholar  * Hainsworth JD _ et al_. (2007) Phase II trial of bevacizumab and erlotinib

in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. _J Clin Oncol_ 25 (Suppl): S1747–S1754 Article  Google Scholar  * Preston _ et al_. (2006) Multitargeted

inhibition of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways. A phase I study of cetuximab (C), erlotinib (E) and bevacizumab in

carcinomas with solid tumors [abstract #3005]. _J Clin Oncol_ 24 * Bendell JC _ et al_. (2007) Results of a phase I study of bevacizumab (BV), everolimus (EV), and erlotinib (E) in patients

with advanced solid tumor [abstract #3548]. _J Clin Oncol_ 25 Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * G Tortora is Associate Professor of Medical Oncology and

Director of the Clinical Unit and Laboratories of Molecular Therapy at the University of Naples Federico II, Naples, F Ciardiello is Associate Professor of Medical Oncology and Head of the

Laboratories of Cancer Therapy at the Second University of Naples, Giampaolo Tortora & Fortunato Ciardiello * G Gasparini is Director and Head of the Division of Medical Oncology at the

San Filippo Neri Hospital, Rome, Italy., Giampietro Gasparini Authors * Giampaolo Tortora View author publications You can also search for this author inPubMed Google Scholar * Fortunato

Ciardiello View author publications You can also search for this author inPubMed Google Scholar * Giampietro Gasparini View author publications You can also search for this author inPubMed 

Google Scholar CORRESPONDING AUTHOR Correspondence to Giampaolo Tortora. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RIGHTS AND PERMISSIONS

Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Tortora, G., Ciardiello, F. & Gasparini, G. Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale,

preclinical studies and clinical applications. _Nat Rev Clin Oncol_ 5, 521–530 (2008). https://doi.org/10.1038/ncponc1161 Download citation * Received: 10 July 2007 * Accepted: 10 December

2007 * Published: 01 July 2008 * Issue Date: September 2008 * DOI: https://doi.org/10.1038/ncponc1161 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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