Therapeutic control and resistance of the EGFR-driven signaling network in  glioblastoma.

EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (ErbB Receptors); Animals; Drug Resistance, Neoplasm; ErbB Receptors/genetics/metabolism; Glioblastoma/genetics/metabolism/pathology/therapy; Humans; Signal Transduction

Abstract :

[en] The alteration of the epidermal growth factor receptor (EGFR)-driven signaling network is a characteristic feature of glioblastomas (GBM), and its inhibition represents a treatment strategy. However, EGFR-targeted interventions have been largely ineffective. Complex perturbations in this system are likely to be central to tumor cells with high adaptive capacity and resistance to therapies. We review key concepts and mechanisms relevant to EGFR-targeted treatment resistance at a systems level. Our understanding of treatment resistance as a systems-level phenomenon is necessary to develop effective therapeutic options for GBM patients. This is allowing us to go beyond the notion of therapeutic targets as single molecular components, into strategies that can weaken cancer signaling robustness and boost inherent network-level vulnerabilities.

Disciplines :

Oncology

Author, co-author :

AZUAJE, Francisco ; Department of Oncology, NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg. Francisco.Azuaje@lih.lu.

Tiemann, Katja; Department of Oncology, NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg. Katja.Tiemann@lih.lu.

NICLOU, Simone P. ; Department of Oncology, NorLux Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH), Luxembourg, Luxembourg. Simone.Niclou@lih.lu.

External co-authors :

yes

Language :

English

Title :

Therapeutic control and resistance of the EGFR-driven signaling network in glioblastoma.

Publication date :

31 March 2015

Journal title :

Cell Communication and Signaling

eISSN :

1478-811X

Publisher :

BioMed Central, London, United Kingdom

Volume :

Pages :

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBilu :

since 23 February 2024

Statistics

Number of views

77 (1 by Unilu)

Number of downloads

18 (0 by Unilu)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, et al. Amplification and overexpression of the EGF receptor gene in primary human glioblastomas. J Cell Sci Suppl. 1985;3:161-72.
Lee JC1, Vivanco I, Beroukhim R, Huang JH, Feng WL, DeBiasi RM, et al. Epidermal growth factor receptor activation in glioblastoma through novel missense mutations in the extracellular domain. PLoS Med. 2006;3:e485.
Vivanco I, Robins HI, Rohle D, Campos C, Grommes C, Nghiemphu PL, et al. Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov. 2012;2:458-71.
Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64:479-89.
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-8.
Fenton TR, Nathanson D, Ponte De Albuquerque C, Kuga D, Iwanami A, Dang J, et al. Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. Proc Natl Acad Sci U S A. 2012;109:14164-9.
Chong CR, Jänne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19:1389-400.
Nakada M, Kita D, Watanabe T, Hayashi Y, Hamada JI. The mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma. Brain Tumor Pathol. 2014;31:198-207.
van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009;27:1268-74.
Fan QW, Cheng C, Knight ZA, Haas-Kogan D, Stokoe D, James CD, et al. EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci Signal. 2009;2:ra4.
Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012-24.
Lemmon MA, Schlessinger J, Ferguson KM. The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb Perspect Biol. 2014;6:a020768.
Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125:1137-49.
Schlessinger J. Receptor tyrosine kinases: legacy of the first two decades. Cold Spring Harb Perspect Biol. 2014;6:a008912.
Schlessinger J, Lemmon MA. SH2 and PTB domains in tyrosine kinase signaling. Sci STKE. 2003;2003:RE12.
Pawson T. Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell. 2004;116:191-203.
Lemmon MA, Schlessinger J. Cell signalling by receptor tyrosine kinases. Cell. 2010;141:1117-34.
Xu GF, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell. 1990;63:835-41.
Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hematologic malignancies. Blood. 2012;120:3397-406.
Levy DE, Lee CK. What does STAT3 do? J Clin Invest. 2002;109:1143-8.
Montgomery RB, Moscatello DK, Wong AJ, Cooper JA, Stahl WL. Differential modulation of mitogen-activated protein (MAP) kinase/extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. J Biol Chem. 1995;270:30562-6.
Huang PH, Xu AM, White FM. Oncogenic EGFR signaling networks in glioma. Sci Signal. 2009;2:re6.
Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol. 2001;2:127-37.
Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res. 2005;11:1462-6.
Wong AJ, Bigner SH, Bigner DD, Kinzler KW, Hamilton SR, Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A. 1987;84:6899-903.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98-110.
Ekstrand AJ, Sugawa M, James CD, Collins VP. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc Natl Acad USA. 1992;89:4309-13.
Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992;89:2965-9.
Frederick L, Wang XY, Eley G, James CD. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res. 2000;60:1383-7.
Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A. 1994;91:7727-31.
Roth P, Weller M. Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro Oncol. 2014;16 Suppl 8:viii14-9.
Pedersen MW, Pedersen N, Ottesen LH, Poulsen HS. Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII. Br J Cancer. 2005;93:915-23.
Gao Q, Lei T, Ye F. Therapeutic targeting of EGFR-activated metabolic pathways in glioblastoma. Expert Opin Investig Drugs. 2013;22:1023-40.
Agarwal S, Manchanda P, Vogelbaum MA, Ohlfest JR, Elmquist WF. Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos. 2013;41:33-9.
Hegi ME, Diserens AC, Bady P, Kamoshima Y, Kouwenhoven MC, Delorenzi M, et al. Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib-a phase II trial. Mol Cancer Ther. 2011;10:1102-12.
Kitano H. Cancer robustness: tumour tactics. Nature. 2003;426:125.
Kitano H. Biological robustness. Nat Rev Genet. 2004;5:826-37.
Niederst MJ, Engelman JA. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci Signal. 2013;6:re6.
Rebecca VW, Smalley KS. Change or die: targeting adaptive signaling to kinase inhibition in cancer cells. Biochem Pharmacol. 2014;91:417-25.
Wiley HS. Open questions: the disrupted circuitry of the cancer cell. BMC Biol. 2014;12:88.
Westin JR. Busting robustness: using cancer's greatest strength to our advantage. Future Oncol. 2015;11:73-7.
Xu AM, Huang PH. Receptor tyrosine kinase coactivation networks in cancer. Cancer Res. 2010;70:3857-60.
Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318:287-90.
Qian F, Engst S, Yamaguchi K, Yu P, Won KA, Mock L, et al. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res. 2009;69:8009-16.
Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009;69:6871-8.
Feng H, Hu B, Jarzynka MJ, Li Y, Keezer S, Johns TG, et al. Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis. Proc Natl Acad Sci U S A. 2012;109:3018-23.
Feng H, Lopez GY, Kim CK, Alvarez A, Duncan CG, Nishikawa R, et al. EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis. J Clin Invest. 2014;124:3741-56.
Fortin Ensign SP, Mathews IT, Symons MH, Berens ME, Tran NL. Implications of Rho GTPase signaling in glioma cell invasion and tumor progression. Front Oncol. 2013;3:241.
Ramis G, Thomàs-Moyà E, Fernández de Mattos S, Rodríguez J, Villalonga P. EGFR inhibition in glioma cells modulates Rho signaling to inhibit cell motility and invasion and cooperates with temozolomide to reduce cell growth. PLoS One. 2012;7:e38770.
Kwiatkowska A, Didier S, Fortin S, Chuang Y, White T, Berens ME, et al. The small GTPase RhoG mediates glioblastoma cell invasion. Mol Cancer. 2012;11:65.
Kusne Y, Carrera-Silva EA, Perry AS, Rushing EJ, Mandell EK, Dietrich JD, et al. Targeting aPKC disables oncogenic signaling by both the EGFR and the proinflammatory cytokine TNFα in glioblastoma. Sci Signal. 2014;7:ra75.
Huang PH, Mukasa A, Bonavia R, Flynn RA, Brewer ZE, Cavenee WK, et al. Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci U S A. 2007;104:12867-72.
Simeone P, Trerotola M, Urbanella A, Lattanzio R, Ciavardelli D, Di Giuseppe F, et al. A unique four-hub protein cluster associates to glioblastoma progression. PLoS One. 2014;9:e103030.
Avraham R, Yarden Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol. 2011;12:104-17.
Kholodenko BN. Cell-signalling dynamics in time and space. Nat Rev Mol Cell Biol. 2006;7:165-76.
Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J. The transcriptional response to Raf activation is almost completely dependent on Mitogen-activated Protein Kinase Kinase activity and shows a major autocrine component. Mol Biol Cell. 2004;15:3450-63.
Amit I, Citri A, Shay T, Lu Y, Katz M, Zhang F, et al. A module of negative feedback regulators defines growth factor signaling. Nat Genet. 2007;2007(39):503-12.
Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J. 2004;23:3270-81.
Shilo BZ. Regulating the dynamics of EGF receptor signaling in space and time. Development. 2005;132:4017-27.
Stutz MA, Shattuck DL, Laederich MB, Carraway 3rd KL, Sweeney C. LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII. Oncogene. 2008;27:5741-52.
Johansson M, Oudin A, Tiemann K, Bernard A, Golebiewska A, Keunen O, et al. The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status. Neuro Oncol. 2013;15:1200-11.
Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature. 2012;483:100-3.
Suh SS, Yoo JY, Nuovo GJ, Jeon YJ, Kim S, Lee TJ, et al. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme. Proc Natl Acad Sci U S A. 2012;109:5316-21.
Li L, Chakraborty S, Yang CR, Hatanpaa KJ, Cipher DJ, Puliyappadamba VT, et al. An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII. Oncogene. 2014;33:4253-64.
Sorkin A, Goh LK. Endocytosis and intracellular trafficking of ErbBs. Exp Cell Res. 2009;315:683-96.
Von Zastrow M, Sorkin A. Signaling on the endocytic pathway. Curr Opin Cell Biol. 2007;19:436-45.
Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 2012;28:124-34.
Lin SY, Makino K, Xia W, Matin A, Wen Y, Kwong KY, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol. 2011;3:802-8.
Lo HW, Cao X, Zhu H, Ali-Osman F. Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes. Mol Cancer Res. 2010;8:232-45.
Cao X, Zhu H, Ali-Osman F, Lo HW. EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: a potential mechanism of EGFR-driven antagonism of apoptosis. Mol Cancer. 2011;10:26.
Wang DY, Cardelli L, Phillips A, Piterman N, Fisher J. Computational modeling of the EGFR network elucidates control mechanisms regulating signal dynamics. BMC Syst Biol. 2009;3:118.
Fan QW, Cheng CK, Gustafson WC, Charron E, Zipper P, Wong RA, et al. EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell. 2013;24:438-49.
Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995;80:179-85.
Purvis JE, Lahav G. Encoding and decoding cellular information through signaling dynamics. Cell. 2013;152:945-56.
Dikic I, Giordano S. Negative receptor signalling. Curr Opin Cell Biol. 2003;15:128-35.
Lauriola M, Enuka Y, Zeisel A, D'Uva G, Roth L, Sharon-Sevilla M, et al. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment. Nat Commun. 2014;5:5073.
Kitano H. Violations of robustness trade-offs. Mol Syst Biol. 2010;6:384.
Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505-16.
Harris AL. Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38-47.
Hardee ME, Zagzag D. Mechanisms of glioma-associated neovascularization. Am J Pathol. 2012;181:1126-41.
McDermott U, Pusapati RV, Christensen JG, Gray NS, Settleman J. Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency. Cancer Res. 2010;70:1625-34.
Trusolino L, Bertotti A. Compensatory pathways in oncogenic kinase signaling and resistance to targeted therapies: six degrees of separation. Cancer Discov. 2012;2:876-80.
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487:505-9.
Zhang KL, Han L, Chen LY, Shi ZD, Yang M, Ren Y, et al. Blockage of a miR-21/EGFR regulatory feedback loop augments anti-EGFR therapy in glioblastomas. Cancer Lett. 2014;342:139-49.
Siebzehnrubl FA, Silver DJ, Tugertimur B, Deleyrolle LP, Siebzehnrubl D, Sarkisian MR, et al. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Mol Med. 2013;5:1196-212.
Azmi AS, Wang Z, Philip PA, Mohammad RM, Sarkar FH. Proof of concept: network and systems biology approaches aid in the discovery of potent anticancer drug combinations. Mol Cancer Ther. 2010;9:3137-44.
Ferrarelli LK. Focus issue: networking cancer treatment strategies. Sci Signal. 2013;6:eg5.
Miller ML, Molinelli EJ, Nair JS, Sheikh T, Samy R, Jing X, et al. Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets. Sci Signal. 2013;6:ra85.
Meyer AS, Miller MA, Gertler FB, Lauffenburger DA. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Sci Signal. 2013;6:ra66.
Wan X, Corn PG, Yang J, Palanisamy N, Starbuck MW, Efstathiou E, et al. Prostate cancer cell-stromal cell crosstalk via FGFR1 mediates antitumor activity of dovitinib in bone metastases. Sci Transl Med. 2014;6:252ra122.
Birtwistle MR, Hatakeyama M, Yumoto N, Ogunnaike BA, Hoek JB, Kholodenko BN. Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses. Mol Syst Biol. 2007;3:144.
Kholodenko BN, Demin OV, Moehren G, Hoek JB. Quantification of short term signaling by the epidermal growth factor receptor. J Biol Chem. 1999;274:30169-81.
Samaga R, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Klamt S. The logic of EGFR/ErbB signaling: theoretical properties and analysis of high-throughput data. PLoS Comput Biol. 2009;5:e1000438.
Kim J, Vandamme D, Kim JR, Munoz AG, Kolch W, Cho KH. Robustness and evolvability of the human signaling network. PLoS Comput Biol. 2014;10:e1003763.
Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;1:2005.0010.