The Insulin-like Growth Factor System As a Potential Therapeutic Target in Gastrointestinal Stromal Tumors

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2008 Sep 27

PMID 18818517

Citations 20

Authors

Martin G Belinsky

Lori Rink

Kathy Q Cai

Michael F Ochs

Burton Eisenberg

Min Huang

Margaret von Mehren

Andrew K Godwin

Affiliations

Soon will be listed here.

Abstract

The majority of gastrointestinal stromal tumors (GISTs) are characterized by oncogenic gain-of-function mutations in the receptor tyrosine kinase (RTK) c-KIT with a minority in PDGFRalpha. Therapy for GISTs has been revolutionized by the use of the selective tyrosine kinase inhibitor imatinib mesylate (IM). For the subset (approximately 10-15%) of GISTs that lack oncogenic mutations in these receptors, the genetic changes driving tumorigenesis are unknown. We recently reported that the gene encoding the insulin-like growth factor 1 receptor (IGF-1R) is amplified in a subset of GISTs, and the IGF-1R protein is overexpressed in wild-type and pediatric GISTs. In this report we present a more complete picture of the involvement of components of the insulin-like growth factor-signaling pathway in the pathogenesis of GISTs. We also discuss how the IGF pathway may provide additional molecular targets for the treatment of GISTs that respond poorly to IM therapy.

Citing Articles

Update on Molecular Genetics of Gastrointestinal Stromal Tumors.

Brcic I, Argyropoulos A, Liegl-Atzwanger B Diagnostics (Basel). 2021; 11(2).

PMID: 33525726 PMC: 7912114. DOI: 10.3390/diagnostics11020194.

The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor.

Liu P, Tan F, Liu H, Li B, Lei T, Zhao X Onco Targets Ther. 2020; 13:2433-2447.

PMID: 32273716 PMC: 7102917. DOI: 10.2147/OTT.S241331.

Downregulation of lncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation.

Yan J, Chen D, Chen X, Sun X, Dong Q, Hu C Braz J Med Biol Res. 2019; 52(6):e8399.

PMID: 31166382 PMC: 6556970. DOI: 10.1590/1414-431x20198399.

Lentivirus-mediated RNAi knockdown of insulin-like growth factor-1 receptor inhibits the growth and invasion of hepatocellular carcinoma via down-regulating midkine expression.

Bie C, Liu X, Cao M, Huang Q, Tang H, Wang M Oncotarget. 2016; 7(48):79305-79318.

PMID: 27813495 PMC: 5346715. DOI: 10.18632/oncotarget.13027.

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor.

Alturkmani H, Pessetto Z, Godwin A Expert Opin Investig Drugs. 2015; 24(8):1045-58.

PMID: 26098203 PMC: 4594857. DOI: 10.1517/13543784.2015.1046594.

References

Wu Y, Cui K, Miyoshi K, Hennighausen L, Green J, Setser J . Reduced circulating insulin-like growth factor I levels delay the onset of chemically and genetically induced mammary tumors. Cancer Res. 2003; 63(15):4384-8. View

Hopfner M, Huether A, Sutter A, Baradari V, Schuppan D, Scherubl H . Blockade of IGF-1 receptor tyrosine kinase has antineoplastic effects in hepatocellular carcinoma cells. Biochem Pharmacol. 2006; 71(10):1435-48. DOI: 10.1016/j.bcp.2006.02.006. View

Maloney E, McLaughlin J, Dagdigian N, Garrett L, Connors K, Zhou X . An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res. 2003; 63(16):5073-83. View

Heinrich M, Corless C, Demetri G, Blanke C, von Mehren M, Joensuu H . Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003; 21(23):4342-9. DOI: 10.1200/JCO.2003.04.190. View

Debiec-Rychter M, Dumez H, Judson I, Wasag B, Verweij J, Brown M . Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004; 40(5):689-95. DOI: 10.1016/j.ejca.2003.11.025. View

Duensing A, Medeiros F, McConarty B, Joseph N, Panigrahy D, Singer S . Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene. 2004; 23(22):3999-4006. DOI: 10.1038/sj.onc.1207525. View

Verweij J, Casali P, Zalcberg J, Lecesne A, Reichardt P, Blay J . Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004; 364(9440):1127-34. DOI: 10.1016/S0140-6736(04)17098-0. View

Peyrat J, Bonneterre J, LAURENT J, Louchez M, Amrani S, Leroy-Martin B . Presence and characterization of insulin-like growth factor 1 receptors in human benign breast disease. Eur J Cancer Clin Oncol. 1988; 24(9):1425-31. DOI: 10.1016/0277-5379(88)90332-x. View

Ogawa O, Eccles M, Szeto J, McNoe L, Yun K, Maw M . Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature. 1993; 362(6422):749-51. DOI: 10.1038/362749a0. View

10.

Railo M, von Smitten K, Pekonen F . The prognostic value of insulin-like growth factor-I in breast cancer patients. Results of a follow-up study on 126 patients. Eur J Cancer. 1994; 30A(3):307-11. DOI: 10.1016/0959-8049(94)90247-x. View

11.

Zhan S, Shapiro D, Helman L . Activation of an imprinted allele of the insulin-like growth factor II gene implicated in rhabdomyosarcoma. J Clin Invest. 1994; 94(1):445-8. PMC: 296329. DOI: 10.1172/JCI117344. View

12.

Kalebic T, Tsokos M, Helman L . In vivo treatment with antibody against IGF-1 receptor suppresses growth of human rhabdomyosarcoma and down-regulates p34cdc2. Cancer Res. 1994; 54(21):5531-4. View

13.

Kabarowski J, Allen P, Wiedemann L . A temperature sensitive p210 BCR-ABL mutant defines the primary consequences of BCR-ABL tyrosine kinase expression in growth factor dependent cells. EMBO J. 1994; 13(24):5887-95. PMC: 395564. DOI: 10.1002/j.1460-2075.1994.tb06934.x. View

14.

Yang X, Beamer W, Huynh H, Pollak M . Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation. Cancer Res. 1996; 56(7):1509-11. View

15.

Lopez-Ilasaca M, Li W, Uren A, Yu J, Kazlauskas A, Gutkind J . Requirement of phosphatidylinositol-3 kinase for activation of JNK/SAPKs by PDGF. Biochem Biophys Res Commun. 1997; 232(2):273-7. DOI: 10.1006/bbrc.1997.6289. View

16.

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S . Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. DOI: 10.1126/science.279.5350.577. View

17.

Kalebic T, Blakesley V, Slade C, Plasschaert S, LeRoith D, Helman L . Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R. Int J Cancer. 1998; 76(2):223-7. DOI: 10.1002/(sici)1097-0215(19980413)76:2<223::aid-ijc9>3.0.co;2-z. View

18.

Wang Y, Wong Y . Sex hormone-induced prostatic carcinogenesis in the noble rat: the role of insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in the development of prostate cancer. Prostate. 1998; 35(3):165-77. DOI: 10.1002/(sici)1097-0045(19980515)35:3<165::aid-pros2>3.0.co;2-g. View

19.

Mira E, Manes S, Lacalle R, Marquez G, Martinez-A C . Insulin-like growth factor I-triggered cell migration and invasion are mediated by matrix metalloproteinase-9. Endocrinology. 1999; 140(4):1657-64. DOI: 10.1210/endo.140.4.6623. View

20.

Atfi A, Prunier C, Mazars A, Defachelles A, Cayre Y, Gespach C . The oncogenic TEL/PDGFR beta fusion protein induces cell death through JNK/SAPK pathway. Oncogene. 1999; 18(26):3878-85. DOI: 10.1038/sj.onc.1202734. View