Abstract
Neoplastic transformation is often related to abnormal activation of growth factor receptors and their signaling pathways. The concept of targeting specific tumorigenic receptors and/or signaling molecules has been validated by the development and successful clinical application of drugs acting against the epidermal growth factor receptor 2 (HER2/neu, Erb2), the epidermal growth factor receptor 1 (EGFR, HER1), the Brc-Abl kinase, the platelet-derived growth factor receptor, and c-kit. This review will focus on the next promising therapeutic target, the insulin-like growth factor I receptor (IGF-IR). IGF-IR has been implicated in a number of neoplastic diseases, including several common carcinomas. From a pharmaceutical standpoint, of particular importance is that IGF-IR appears to be required for many transforming agents (genetic, viral, chemical) to act, but is not obligatory for the function of normal adult cells. The tumorigenic potential of IGF-IR is mediated through its antiapoptotic and transforming signaling, and in some cases through induction of prometastatic pathways. Preclinical studies demonstrated that downregulation of IGF-IR reversed the neoplastic phenotype and sensitized cells to antitumor treatments. The strategies to block IGF-IR function employed anti-IGF-IR antibodies, small-molecule inhibitors of the IGF-IR tyrosine kinase, antisense oligodeoxynucleotides and antisense RNA, small inhibitory RNA, triple helix, dominant-negative mutants, and various compounds reducing ligand availability. The experience with these strategies combined with the knowledge gained with current anti-growth factor receptor drugs should streamline the development of anti-IGF-IR therapeutics.
Similar content being viewed by others
References
Adachi Y, Lee CT, Coffee K, Yamagata N, Ohm JE, Park KH, Dikov MM, Nadaf SR, Arteaga CL and Carbone DP . (2002). Gastroenterology, 123, 1191–1204.
Adams TE, Epa VC, Garrett TP and Ward CW . (2000). Cell. Mol. Life Sci., 57, 1050–1093.
Andrews DW, Resnicoff M, Flanders AE, Kenyon L, Curtis M, Merli G, Baserga R, Iliakis G and Aiken RD . (2001). J. Clin. Oncol., 19, 2189–2200.
Arteaga CL . (1992). Breast Cancer Res. Treat., 22, 101–116.
Arteaga CL . (2003). Exp. Cell Res., 284, 122–130.
Arteaga CL, Kitten LJ, Coronado EB, Jacobs S, Kull Jr FC, Allred DC and Osborne CK . (1989). J. Clin. Invest., 84, 1418–1423.
Bartucci M, Morelli C, Mauro L, Ando' S and Surmacz E . (2001). Cancer Res., 61, 6747–6754.
Baserga R . (1994). Cell, 79, 927–930.
Baserga R . (1995). Cancer Res., 55, 249–252.
Baserga R . (1996). Trends Biotechnol., 14, 150–152.
Baserga R . (1997). Exp. Cell Res., 236, 1–3.
Baserga R . (1998). Hormones and Growth Factors in Development and Neoplasia Dickson R, Salomon DS (eds). Wiley-Liss: New York, pp. 269–287.
Blakesley VA, Kalebic T, Helman LJ, Stannard B, Faria TN, Roberts Jr CT and LeRoith D . (1996). Endocrinology, 137, 410–417.
Blum G, Gazit A and Levitzki A . (2000). Biochemistry, 39, 15705–15712.
Bohula EA, Salisbury AJ, Sohail M, Playford MP, Riedemann J, Southern EM and Macaulay VM . (2003). J Biol. Chem. 278, 15991–15997.
Brazil DP, Park J and Hemmings BA. . (2002). Cell, 111, 293–303.
Brodt P, Fallavollita L, Khatib AM, Samani AA and Zhang D . (2001). J Biol. Chem., 276, 33608–33615.
Brodt P, Samani A and Navab R . (2000). Biochem. Pharmacol., 60, 1101–1107.
Burfeind P, Chernicky CL, Rininsland F and Ilan J . (1996). Proc. Natl. Acad. Sci. USA, 93, 7263–7268.
Burgaud JL, Resnicoff M and Baserga R . (1995). Biochem. Biophys. Res. Commun., 214, 475–481.
Butler AA, Blakesley VA, Poulaki V, Tsokos M, Wood TL and LeRoith D . (1998). Cancer Res., 58, 3021–3027.
Chernicky CL, Yi L, Tan H, Gan SU and Ilan J . (2000). Cancer Gene Ther., 7, 384–395.
Coppola D, Saunders B, Fu L, Mao W and Nicosia SV . (1999). Cancer Res., 59, 3264–3270.
D'Ambrosio C, Ferber A, Resnicoff M and Baserga R . (1996). Cancer Res., 56, 4013–4020.
De Leon DD, Wilson DM, Powers M and Rosenfeld RG . (1992). Growth Factors, 6, 327–336.
De Meyts P and Whittaker J . (2002). Nat. Rev. Drug Discov., 1, 769–783.
Djavan B, Waldert M, Seitz C and Marberger M . (2001). World J. Urol., 19, 225–233.
Doerr M and Jones J . (1996). J. Biol. Chem., 271, 2443–2447.
Druckmann R and Rohr UD . (2002). Maturitas, 41 (Suppl. 1), S65–S83.
Druker BJ . (2002). Eur. J. Cancer, 38 (Suppl. 5), S70–S76.
Dunn SE, Ehrlich M, Sharp NJH, Reiss K, Solomon G, Hawkins R, Baserga R and Barrett JC . (1998). Cancer Res., 58, 3353–3361.
Dunn SE, Kari FW, French J, Leininger JR, Travlos G, Wilson R and Barrett JC . (1997). Cancer Res., 57, 4667–4672.
Dunn SE, Torres JV, Oh JS, Cykert DM and Barrett JC . (2001). Cancer Res., 61, 1367–1374.
Favelyukis S, Till JH, Hubbard SR and Miller WT . (2001). Nat. Struct. Biol., 8, 1058–1063.
Fry DW . (2003). Exp. Cell Res., 284, 131–139.
Giovannucci E . (2001). J. Nutr., 131 (Suppl), 3109S–3120S.
Guo N, Ye JJ, Liang SJ, Mineo R, Li SL, Giannini S, Plymate SR, Sikes RA and Fujita-Yamaguchi Y . (2003). Growth Horm. IGF Res., 13, 44–53.
Guvakova M and Surmacz E . (1999). Exp. Cell Res., 251, 244–255.
Hailey J, Maxwell E, Koukouras K, Bishop WR, Pachter JA and Wang Y . (2002). Mol. Cancer Ther., 1, 1349–1353.
Harries M and Smith I . (2002). Endocr. Relat. Cancer, 9, 75–85.
Hernandez-Boluda JC and Cervantes F . (2002). Drugs Today, 38, 601–613.
Hill MM and Hemmings BA . (2002). Pharmacol. Ther., 93, 243–251.
Holbro T, Civenni G and Hynes NE . (2003). Exp. Cell Res., 284, 99–110.
Hongo A, D'Ambrosio C, Miura M, Morrione A and Baserga R . (1996). Oncogene, 12, 1231–1238.
Hongo A, Yumet G, Resnicoff M, Romano G, O' Connor R and Baserga R . (1998). Cancer Res., 58, 2477–2484.
Jacobs S, Cook S, Svoboda ME and Van Wyk JJ . (1986). Endocrinology, 118, 223–226.
Kalebic T, Blakesley V, Slade C, Plasschaert S, LeRoith D and Helman LJ . (1998). Int. J. Cancer, 76, 223–227.
Kalebic T, Tsokos M and Helman LJ . (1994). Cancer Res., 54, 5531–5534.
Kaleko M, Rutter WJ and Miller AD . (1990). Mol. Cell. Biol., 10, 464–473.
Kato H, Faria TN, Stannard B, Roberts Jr CT and LeRoith D . (1993). J. Biol. Chem., 268, 2655–2661.
Korc M . (1998). Surg. Oncol. Clin. N. Am., 7, 25–41.
Lee CT, Park KH, Adachi Y, Seol JY, Yoo CG, Kim YW, Han SK, Shim YS, Coffee K, Dikov MM and Carbone DP . (2003). Cancer Gene Ther., 10, 57–63.
Lee CT, Wu S, Gabrilovich D, Chen H, Nadaf-Rahrov S, Ciernik IF and Carbone DP . (1996). Cancer Res., 56, 3038–3041.
Levitzki A . (2002). Eur. J. Cancer, 38 (Suppl. 5), S11–S8.
Li SL, Kato J, Paz IB, Kasuya J and Fujita-Yamaguchi Y . (1993). Biochem. Biophys. Res. Commun., 196, 92–98.
Li SL, Liang SJ, Guo N, Wu AM and Fujita-Yamaguchi Y . (2000). Cancer Immunol. Immunother., 49, 243–252.
Liu Y, Lehar S, Corvi C, Payne G and O'Connor R . (1998). Cancer Res., 58, 570–576.
Long L, Navab R and Brodt P . (1998). Cancer Res., 58, 3243–3247.
Lu Y, Zi X, Zhao Y, Mascarenhas D and Pollak M . (2001). J. Natl. Cancer Inst., 93, 1852–1857.
Macaulay VM, Salisbury AJ, Bohula EA, Playford MP, Smorodinsky NI and Shiloh Y . (2001). Oncogene, 20, 4029–4040.
Mauro L, Salerno M, Morelli C, Boterberg T, Bracke ME and Surmacz E . (2003). J. Cell. Physiol., 194, 108–116.
Mauro L, Sisci D, Salerno M, Kim J, Tam T, Guvakova M, Ando S and Surmacz E . (1999). Exp. Cell Res., 252, 439–448.
Mendelsohn J and Baselga J . (2000). Oncogene, 19, 6550–6565.
Mira E, Manes S, Lacalle RA, Marques G and Martinez-AC . (1999). Endocrinology, 140, 1657–1664.
Muller M, Dietel M, Turzynski A and Wiechen K . (1998). Int. J. Cancer, 17, 567–571.
Nakamura K, Hongo A, Kodama J, Miyagi Y, Yoshinouchi M and Kudo T . (2000). Cancer Res., 60, 760–765.
Navab R, Chevet E, Authier F, Di Guglielmo GM, Bergeron JJ and Brodt P . (2001). J. Biol. Chem., 276, 13644–13649.
Neuenschwander S, Roberts Jr CT and LeRoith D . (1995). Endocrinology, 136, 4298–4303.
Nicholson KM and Anderson N . (2002). Cell Signal., 14, 381–395.
O'Connor R . (1998). Adv. Bioch. Engin/Biotech Scheper T (ed), Vol. 62. Springer-Verlag: Berlin, pp. 138–166.
O'Connor R, Fennelly C and Krause D . (2000). Biochem. Soc. Trans., 28, 47–51.
O'Connor R, Kauffmann-Zeh A, Liu Y, Lehar S, Evan GI, Baserga R and Blattler WA . (1997). Mol. Cell. Biol., 17, 427–435.
Pautsch A, Zoephel A, Ahorn H, Spevak W, Hauptmann R and Nar H . (2001). Structure, 9, 955–965.
Pavelic J, Pavelic L, Karadza J, Krizanac S, Unesic J, Spaventi S and Pavelic K . (2002). Mol. Med., 8, 149–157.
Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B and Baserga R . (1999). Mol. Cell. Biol., 19, 7203–7215.
Pietrzkowski Z, Lammers R, Carpenter G, Soderquist AM, Limardo M, Phillips PD, Ullrich A and Baserga R . (1992a). Cell Growth Differ., 3, 199–205.
Pietrzkowski Z, Mulholland G, Gomella L, Jameson BA, Wernicke D and Baserga R . (1993). Cancer Res., 53, 1102–1106.
Pietrzkowski Z, Wernicke D, Porcu P, Jameson BA and Baserga R . (1992b). Cancer Res., 52, 6447–6451.
Pollak M . (2000). Eur. J. Cancer, 36, 1224–1228.
Prager D, Li HL, Asa S and Melmed S . (1994). Proc. Natl. Acad. Sci. USA, 91, 2181–2185.
Reiss K, D'Ambrosio C, Tu X, Tu C and Baserga R . (1998). Clin. Cancer Res., 4, 2647–2655.
Reiss K, Wang JY, Romano G, Tu X, Peruzzi F and Baserga R . (2001a). Oncogene, 20, 490–500.
Reiss K, Tu X, Romano G, Peruzzi F, Wang JY and Baserga R . (2001b). Clin. Cancer Res., 7, 2134–2144.
Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL, Kajstura J, Rubin R, Zoltick P and Baserga R . (1995b). Cancer Res., 55, 2463–2469.
Resnicoff M, Burgaud JL, Rotman HL, Abraham D and Baserga R . (1995a). Cancer Res., 55, 3739–3741.
Resnicoff M, Sell C, Rubini M, Coppola D, Ambrose D, Baserga R and Rubin R . (1994). Cancer Res., 54, 2218–2222.
Rininsland F, Johnson TR, Chernicky CL, Schulze E, Burfeind P and Ilan J . (1997). Proc. Natl. Acad. Sci. USA, 94, 5854–5859.
Romano G, Frisco M, Zanocco-Marani T, Peruzzi F, Valentinis B and Baserga R . (1999). J. Cell. Biochem., 72, 294–310.
Sachdev D, Li SL, Hartell JS, Fujita-Yamaguchi Y, Miller JS and Yee D . (2003). Cancer Res., 63, 627–635.
Sachdev D and Yee D . (2001). Endocr. Relat. Cancer, 8, 197–209.
Scharf JG, Dombrowski F and Ramadori G . (2001). Mol. Pathol., 54, 138–144.
Scotlandi K, Avnet S, Benini S, Manara MC, Serra M, Cerisano V, Perdichizzi S, Lollini PL, De Giovanni C, Landuzzi L and Picci P . (2002). Int. J. Cancer, 101, 11–16.
Scotlandi K, Benini S, Nanni P, Lollini PL, Nicoletti G, Landuzzi L, Serra M, Manara MC, Picci P and Baldini N . (1998). Cancer Res., 58, 4127–4131.
Seely BL, Samimi G and Webster NJ . (2002). BMC Cancer, 2, 15–25.
Shapiro DN, Jones BG, Shapiro LH, Dias P and Houghton PJ . (1994). J. Clin. Invest., 94, 1235–1242.
Shaw LM . (2001). Mol. Cell. Biol., 21, 5082–5093.
Shawver LK, Slamon D and Ullrich A . (2002). Cancer Cell, 1, 117–123.
Shepherd PR, Withers D and Siddle K . (1998). Biochem. J., 333, 471–490.
Surmacz E . (2000). J. Mammary Gland Biol. Neopl., 5, 95–105.
Surmacz E, Sell C, Swantek J, Kato H, Roberts Jr. CT, LeRoith D and Baserga R . (1995). Exp. Cell Res., 218, 370–380.
Trojan LA, Kopinski P, Wei MX, Ly A, Glogowska A, Czarny J, Shevelev A, Przewlocki R, Henin D and Trojan J . (2002). Acta Biochim. Pol., 49, 979–990.
Ullrich A, Gray A, Tarn AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E, Jacobs S, Francke U, Ramachandran J and Fujita-Yamaguchi Y . (1986). EMBO J., 5, 2503–2512.
Vuori K and Ruoslahti E . (1994). Science, 266, 1576–1576.
White MF . (1998). Mol. Cell. Biochem., 182, 3–11.
White MF . (2002). Am. J. Physiol. Endocrinol. Metab., 283, E413–422.
Yee D . (2002). Semin. Oncol., 29 (Suppl 11), 86–95.
Zhang D and Brodt P . (2003). Oncogene, 22, 974–982.
Zia F, Jacobs S, Kull Jr F, Cuttitta F, Mulshine JL and Moody TW . (1996). J. Cell. Biochem. Suppl., 24, 269–275.
Zong CS, Chan J, Levy DE, Horvath C, Sadowski HB and Wang LH . (2000). J. Biol Chem., 275, 15099–15105.
Zong CS, Zeng L, Jiang Y, Sadowski HB and Wang LH . (1998). J. Biol. Chem., 273, 28065–22872.
Acknowledgements
This work was supported by DOD Breast Cancer Research Program DAMD-17-99-1-9407.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Surmacz, E. Growth factor receptors as therapeutic targets: strategies to inhibit the insulin-like growth factor I receptor. Oncogene 22, 6589–6597 (2003). https://doi.org/10.1038/sj.onc.1206772
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206772
- Springer Nature Limited
Keywords
This article is cited by
-
Cancer-associated fibroblasts promote cisplatin resistance in bladder cancer cells by increasing IGF-1/ERβ/Bcl-2 signalling
Cell Death & Disease (2019)
-
Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling
Oncogene (2016)
-
Extracellular vimentin interacts with insulin-like growth factor 1 receptor to promote axonal growth
Scientific Reports (2015)
-
In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib
Breast Cancer Research and Treatment (2015)
-
The effect of IGF-I receptor blockade for human esophageal squamous cell carcinoma and adenocarcinoma
Tumor Biology (2014)