Monoclonal antibodies in regulation of signal transduction of Epidermal Growth Factor Receptor (EGFR) pathway in cancer cells
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Zakład Biotechnologii i Inżynierii Genetycznej, Wydział Farmaceutyczny z Oddziałem Medycyny Laboratoryjnej w Sosnowcu, Śląski Uniwersytet Medyczny w Katowicach
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Ilona Bednarek   

Zakład Biotechnologii i Inżynierii Genetycznej, Wydział Farmaceutyczny z Oddziałem Medycyny Laboratoryjnej w Sosnowcu, Śląski Uniwersytet Medyczny w Katowicach, ul. Jedności 8, 41-200 Sosnowiec
Ann. Acad. Med. Siles. 2018;72:12-20
In recent years intensive research has been dedicated to the Epidermal Growth Factor Receptor (EGFR) due to its significant role in the pathogenesis of malignant tumors. In many types of cancers intracellular pathways modulated by EGFR have been identified as crucial factors influencing tumor survival and development. On the other hand, EGFR has also been shown to be a promising molecular target for potential therapeutic agents. Attempts to modify the signal transduction exerted by EGF have been made either by blocking the activity of certain elements of the EGFR pathway or by direct inhibition of the EGF receptor itself. It has also been demonstrated that the use of monoclonal antibodies to block the EGF receptor increases the effectiveness of conventional anticancer agents such as cisplatin. Thus, many anticancer therapies based on inhibitors of the selected components of the EGFR signaling pathway have been established, and many of them apply monoclonal antibodies.
Zhang J., Saba N.F. Chen G., Shin D.M. Targeting HER (ERBB) signaling in head and neck cancer: An essential update. Mol. Aspects. Med. 2015; 45: 74–86.
Tomas A., Futter C.E., Eden E.R. EGR receptor trafficking: consequences for signaling and cancer. Trends Cell Biol. 2014; 24(1): 26–34.
Wieduwilt M.J., Moasser M.M. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell. Mol. Life Sci. 2008; 65(10): 1566–1584.
Goffin J.R., Zbuk K. Epidermal Growth Factor Receptor: Pathway, Therapies, and Pipeline. Clin. Ther. 2013; 35(9): 1282–1303.
Włodarkiewicz A., Sobjanek M., Michajłowski I., Nałęcz D., Niekra M., Michajłowski D. Strategie molekularne w leczeniu raków skóry. Prz. Dermatol. 2012; 99(2): 120–124.
Akinleye A., Iragavarapu C., Furqan M., Cang S., Liu D. Novel agents for advanced pancreatic cancer. Oncotarget. 2015; 6(37): 39521–39537.
Daniel P., Małecka-Panas E. Podstawy teoretyczne leczenia nowotworów ukierunkowane na drogi sygnałowe receptora czynników wzrostowych rodziny naskórkowego czynnika wzrostu. Prz. Lek. 2005; 62(8): 804–809.
Khelwatty S.A., Essapen S., Seddon A.M., Fan Z., Modjtahedi H. Acquired resistance to anti-EGFR mAB ICR62 in cancer cells is accompanied by an increased EGFR expression, HER-2/HER-3 signalling and sensitivity to pan HER blockers. Brit. J. Cancer. 2015; 113(7): 1010–1019.
Wang S., Song Y., Liu D. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer. Lett. 2017; 385: 51–54.
Yewale C., Baradia D., Vhora I., Patil S., Misra A. Epidermal growth factor receptor targeting in cancer: A review of trends and strategies. Biomaterials. 2013; 34(34): 8690–8707.
Bozec A., Ebran M., Radovevic-Robin N., Sudaka A., Monteverde M., Toussan N., Etienne-Grimaldi M.C., Nigro C.L., Merlano M., Penault-Llorca F., Milano G. Combination of mTOR and EGFR targeting in an orthotopic xenograft model of head and neck cancer. Laryngoscope 2016; 126(4): E156––E163.
El Guerrab A., Bamdad M., Kwiatkowski F., Bignon Y.J., Penault-Llorca F., Aubel C. Anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors as combination therapy for triple-negative breast cancer. Oncotarget. 2016; 7(45): 73618–73637.
Jeannot V., Busser B., Vanwonterghem L., Michallet S., Ferroudj S., Cokol M., Coll J.L., Ozturk M., Hurbin A. Synergistic activity of vorinostat combined with gefitinib but not with sorafenib in mutant KRAS human non-small cell lung cancers and hepatocarcinoma. Onco. Targets Ther. 2016; 9: 6843–6855.
Vacas E., Munoz-Moreno L., Valenzuela P.L., Prieto J.C., Schally A.V., Carmena M.J., Bajo A.M. Growth hormone-releasing hormone induced transactivation of epidermal growth factor receptor in human triple-negative breast cancer cells. Peptides. 2016; 86: 153–161.
Birkman E.M., Algars A., Lintunen M., Ristamäki R., Sundstrom J., Carpén O. EGFR gene amplification is relatively common and associates with outcome in intestinal adenocarcinoma of the stomach, gastro-oesophageal junction and distal oesophagus. BMC Cancer 2016; 16: 406.
Kowalski D.M., Krzakowski M., Janowicz-Żebrowska A. Hamowanie osi receptora naskórkowego czynnika wzrostu w leczeniu niedrobnokomórkowego raka płuca. Onkol. Prakt. Klin. 2011; 7(4): 177–182.
Xu W., Bi Y., Zhang J., Kong J., Jiang H., Tian M., Li K., Wang B., Chen C., Song F., Pan X., Shi B., Kong X., Gu J., Cai X., Li Z. Synergistic antitumor efficacy against the EGFRvIII+HER+ breast cancers by combining trastuzumab with anti-EGFRvIII antibody CH12. Oncotarget 2015; 6(36): 38840–38853.
Sierko E., Wojtukiewicz M. Interferowanie z funkcją EGFR – nowe możliwości leczenia chorych na glejaki mózgu? Onkol. Prakt. Klin. 2011; 7(4): 215–223.
Artemov A., Aliper A., Korzinkin M., Lezhnina K., Jellen L., Zhukov N., Roumiantsev S., Gaifullin N., Zhavoronkov A., Borisov N., Buzdin A. A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation. Oncotarget 2015; 6(30): 29347–29356.
Seow H.F., Yip W.K., Fifis T. Advances in targeted and immunobased therapies for colorectal cancer in the genomic era. Onco. Targets Ther. 2016; 9: 1899–1920.
Matsunaga Y., Adachi Y., Sasaki Y., Koide H., Motoya M., Nosho K., Takagi H., Yamamoto H., Sasaki S., Arimura Y., Tokino T., Carbone D.P., Imai K., Shinomura Y. The effect of forced expression of mutated K-RAS on gastrointestinal cancer cell lines and the IGF-1R targeting therapy. Mol. Carcinog. 2016; 56(2) : 515–526. DOI: 10.1002/mc.22513.
Wyrwicz L.S., Nowecki Z.I. Panitumumab i hamowanie sygnalizacji osi receptora naskórkowego czynnika wzrostu w leczeniu przerzutowego raka jelita grubego. Onkol. Prakt. Klin. 2010; 6(6): 290–300.
Liccardi G., Hartley J.A., Hochhauser D. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer. Res. 2011; 71(3): 1103–1114.
Ohnishi Y., Yasui H., Kakudo K., Nozaki M. Cetuximab-resistant oral squamous cell carcinoma cells become sensitive in anchorage-independent culture conditions through the activation of the EGFR/AKT pathway. Int. J. Oncol. 2015; 47(6): 2165-2172.
Gracia-Cazaña T., Gonzalez S., Gilaberte Y. Resistance of nonmelanoma skin cancer to nonsurgical treatments. Part I: Topical treatments. Actas Dermosifiliogr. 2016; 107(9): 730–739.
Gracia-Cazaña T., Salazar N., Zamarron A., Mascaraque M, Lucena S.R., Juarranz A. Resistance of nonmelanoma skin cancer to nonsurgical treatments. Part II: Photodynamic therapy, vismodegib, cetuximab, intralesional methotrexate, and radiotherapy. Actas Dermosifiliogr. 2016; 107(9): 740–750.
Amaro A., Mirisola V., Angelini G., Musso A., Tosetti F., Esposito A.I., Perri P., Lanza F., Nasciuti F., Mosci C., Puzone R., Salvi S., Truini M., Poggi A., Pfeffer U. Evidence of epidermal growth factor receptor expression in uveal melanoma: inhibition of epidermal frowth factor-mediated signalling by Gefitinib and Cetuximab triggered antibody-dependent cellular cytotoxicity. Eur. J. Cancer. 2013; 49(15): 3353–3365.
Wollina U. Cetuximab in non-melanoma skin cancer. Expert. Opin. Biol. Th. 2012; 12(7): 949–956.
Szopa W., Burley T.A., Kramer-Marek G., Kaspera W. Diagnostic and therapeutic biomarkers in glioblastoma: Current status and future perspectives. Biomed. Res. Int. 2017; 8013575. DOI: 10.1155/2017/8013575.
Miller J.J., Wen P.Y. Emerging targeted therapies for glioma. Expert Opin. Emerg. Dr. 2016; 14728214.2016.1257609 [dostęp: 12.12.2016].
D’Alessandris Q.G., Montano N., Cenci T., Martini M., Lauretti L., Bianchi F., Larocca L.M., Maira G., Fernandez E., Pallini R. Targeted therapy with bevacizumab and erlotinib tailored to the molecular profile of patients with recurrent glioblastoma. Preliminary experience. Acta. Neurochir. 2013; 155(1): 33–40.
Hicks M.J., Chiuchiolo M.J., Ballon D., Dyke J.P., Aronowitz E., Funato K., Tabar V., Havlicek D., Fan F., Sondhi D., Kaminsky S.M., Crystal R.G. Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma. PLoS. One. 2016; 11(10): e0162978.
Durko Ł., Małecka-Panas E. Nowe strategie leczenia raka trzustki ukierunkowane na ścieżkę sygnałową receptora dla naskórkowego czynnika wzrostu. Gastroenterol. Pol. 2008; 15 (1): 57–61.
Philip P.A., Lutz M.P. Targeting epidermal growth factor receptor-related signaling pathways in pancreatic cancer. Pancreas 2015; 44(7): 1046–1052.
Silvestris N., Gnoni A., Brunetti A.E., Vincenti L., Santini D., Tonini G., Merchionne F., Maiello E., Lorusso V., Nardulli P., Azzariti A., Reni M. Target therapies in pancreatic carcinoma. Curr. Med. Chem. 2014; 21(8): 948–965.
Saif M.W. Advanced stage pancreatic cancer: novel therapeutic options. Expert Rev. Clin. Pharmacol. 2014; 7(4): 487–498.
Sasada T., Azuma K., Ohtake J., Fujimoto Y. Immune responses to epidermal growth factor receptor (EGFR) and their application for cancer treatment. Front. Pharmacol. 2016; 7(405): eCollection 2016.
Nedaeinia R., Avan A., Manian M., Salehi R., Ghayour-Mobarhan M. EGFR as a potential target for the treatment of pancreatic cancer: dilemma and controversies. Curr. Drug Targets 2014; 15(14): 1293–1301.
Esnaola N.F., Chaudhary U.B., O’Brien P., Garrett-Mayer E., Camp E.R., Thomas M.B., Cole D.J., Montero A.J., Hoffman B.J., Romagnuolo J., Orwat K.P., Marshall D.T. Phase 2 trial of induction gemcitabine, oxaliplatin, and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 2014; 88(4): 837–844.
Burtness B., Powell M., Catalano P., Berlin J., Liles D.K., Chapman A.E., Mitchell E., Benson A.B. Randomized phase II trial of irinotecan/docetaxel or irinotecan/docetaxel plus cetuximab for metastatic pancreatic cancer: An eastern cooperative oncology group study. Am. J. Clin. Oncol. 2016; 39(4): 340–345.
Rembielak A.I., Jain P., Jackson A.S., Green M.M., Santorelli G.R., Whitfield G.A., Crellin A., Garcia-Alonso A., Radhakrishna G., Cullen J., Taylor M.B., Swindell R., West C.M., Valle J., Saleem A., Price P.M. Phase II trial of cetuximab and conformal radiotherapy only in locally advanced pancreatic cancer with concurrent tissue sampling feasibility study. Transl. Oncol. 2014; 7(1): 55–64.
Fiore M., Trodella L., Valeri S., Borzomati D., Floreno B., Ippolito E., Trecca P., Trodella L.E., D’Angelillo R.M., Ramella S., Coppola R. Prospec-tive study of cetuximab and gemcitabine in combination with radiation therapy: feasibility and efficacy in locally advanced pancreatic head cancer. Radiat. Oncol. 2015; 10: 255. Doi: 10.1186/s13014-015-0564-8.
Gaborit N., Lindzen M., Yarden Y. Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3. Hum. Vaccin. Immunother. 2016; 12(3): 576–592.
Assenat E., Azria D., Mollevi C., Guimbaud R., Tubiana-Mathieu N., Smith D., Delord J.P., Samalin E., Portales F., Larbouret C., Robert B., Bibeau F., Bleuse J.P., Crapez E., Ychou M., Pelegrin A. Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the ‘THERAPY’ phase 1–2 trial. Oncotarget 2015; 6(14): 12796–12808.
Tai C.J., Huang M.T., Wu C.H., Wang C.K., Tai C.J., Chang C.C., Hsieh C.I., Chang Y.J., Wu C.J., Kuo L.J., Wei P.L., Chen R.J., Chiou H.Y. Combination of two targeted medications (bevacizumab plus cetuximab) improve the therapeutic response of pancreatic carcinoma. Medicine (Baltimore) 2016; 95(15): e3259. Doi: 10.1097/MD.0000000000003259.
Pirker R. EGFR-directed monoclonal antibodies in non-small cell lung cancer. Target Oncol. 2013; 8(1): 47–53.
Chang H., Oh J., Zhang X., Kim Y.J., Lee J.H., Lee C.T., Chung J.H., Lee J.S. EGFR protein expression using a specific intracellular domain antibody and PTEN and clinical outcomes in squamous cel lung cancer patients with EGFR-tyrosine kinase inhibitor therapy. Onco Targets Ther 2016; 9: 5153–5162.
Son D.J., Hong J.E., Ban J.O., Park J.H., Lee H.L., Gu S.M., Hwang J.Y., Jung M.H., Lee D.W., Han S.B., Hong J.T. Synergistic Inhibitory effects of Cetuximab and Cisplatin on Human Colon Cancer Cell Growth via Inhibition of the ERK-Dependent EGF Receptor Signaling Pathway. Biomed. Res. Int. 2015: 397563.
Yang Z.Y., Liu L., Mao C., Wu X.Y., Huang Y.F., Hu X.F., Tang J.L. Chemotherapy with cetuximab versus chemotherapy alone for chemotherapy-naive advanced non-small cell lung cancer. Cochrane Database Syst. Rev. 2014; 17(11): CD009948. Doi:10.1002/14651858.pub2.
Magrini S.M., Buglione M., Corvo R., Pirtoli L., Paiar F., Ponticelli P., Petrucci A., Bacigalupo A., Crociani M., Lastrucci L., Vecchio S., Bonomo P., Pasinetti N., Triggiani L., Cavagnini R., Costa L., Tonoli S., Maddalo M., Grisanti S. Cetuximab and radiotherapy versus cisplatin and radiotherapy for locally advanced head and neck cancer: a randomized phase II trial. J. Clin. Oncol. 2016; 34(5): 427–435.
Bonetta A., Bandera L., Roviello G., Cafaro I., Bottini A., Generali D. Neoadjuvant chemotherapy and radical radiotherapy associated with cetuximab for laryngeal cancer in a pancreas and renal recipient. Anticancer Drugs 2016; 27(5): 470–473.
Misale S., Bozic I., Tong J., Peraza-Penton A., Lallo A., Baldi F., Lin K.H., Truini M., Trusolino L., Bertotti A., Di Nicolantonio F., Nowak M.A., Zhang L., Wood K.C., Bardelli A. Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers. Nat. Commun. 2015; 6(8305): 1–9.
Wyrwicz L.S., Nowecki Z.I. Panitumumab i hamowanie. sygnalizacji osi receptora naskórkowego czynnika wzrostu w leczeniu przerzutowego raka jelita grubego. Onkol. Prakt. Klin. 2010; 6(6): 290–300.
Garcia-Foncillas J. Diaz-Rubio E. Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome. Clin. Transl. Oncol. 2010; 12(8): 533–542.
Schimanski C.C., Staib F. Gohler T., Hebart H., Heike M., Neise M., Rudi J., Geer T., Dingeldein G., Lang C., Ehscheidt P., Flohr T., Josten K.M., Karthaus M., Schmittel A., Wierecky J., Boller E., Indorf M., Worns M.A., Galle P.R., Moehler M. Dermatux: phase IV trial of cetuximab plus FOLFIRI in first-line metastatic colorectal cancer receiving a pre-defined skin care. J. Cancer Res. Clin. Oncol. 2017; 143(6): 1023–1034.
Niesen J., Stein C., Brehm H., Hehmann-Titt G., Fendel R., Melmer G., Fischer R., Barth S. Novel EGFR-specyfic immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities. J. Cancer. Res. Clin. Oncol. 2015; 141(12): 2079–2095.
Trarbach T., Przyborek M., Schleucher N., Heeger S., Lupfert C., Vanhoefer U. Phase I study of matuzumab in combination with 5-fluorouracil, leucovorin and cisplatin (PLF) in patients with advanced gastric and esophagogastric adenocarcinomas. Invest. New Drugs 2013; 31(3): 642–652.
Wang F., Jiang C., Ye Z., Sun Q., Liu T., Xu M., Wu P., Shi K., Long B., Rihito A., Masoto S., Fu Z. Efficacy and safety of nimotuzumab with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma. Oncotarget 2017; 8(43): 75544–75556, DOI: 10.18632/oncotarget.17357.
Li H.M., Li P., Qian Y.J., Wu X., Xie L., Wang F., Zhang H., Liu L. A retrospective paired study: efficacy and toxicity of nimotuzumab versus cisplatin concurrent with radiotherapy in nasopharyngeal carcinoma. BMC Cancer 2016; 16(1): 946.
Wulbrand C., Seidl C., Gaertner F.C., Bruchertseifer F., Morgenstern A., Essler M., Senekowitsch-Schmidtke R. Alpha-particle emitting 213Bi-anti-EGFR immunoconjugates eradicate tumor cells independent of oxygenation. PLoS One 2013; 8(5): e64730. DOI: 10.1371/journal.pone.0064730.
Shapira A., Benhar I. Toxin-based therapeutic approaches. Toxins (Basel). 2010; 2(11): 2519–2583.
Karpel-Massler G., Schmidt U., Unterberg A., Halatsch M. Therapeutic inhibition of the epidermal growth factor receptor in high-grade gliomas: Where do we stand? Mol. Cancer Res. 2009; 7(7): 1000–1012.
Michaelis M., Bliss J., Arnold S.C., Hinsch S., Rothweiler F., Deubzer H.E., Witt O., Langer K., Doerr H.W., Wels W.S., Cinatl J. Cisplatin-resistant neuroblastoma cells express enhanced levels of epidermal growth factor receptor (EGFR) and are sensitive to treatment with EGFR-specific toxins. Clin. Cancer Res. 2008; 14(20): 6531–6537.
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