title: Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy.
abstract: The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic beta cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti-IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti-IGF-1R therapies.
authors.affiliation: Department of Biochemistry and Biophysics, Diabetes Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Danielle B
authors.initials: DB
authors.lastname: Ulanet
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000628:therapy*; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D017527:Receptor, IGF Type 2; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
references.citation: Oncogene. 1999 Apr 15;18(15):2471-9
references.pmid: 10229198
references.citation: Clin Cancer Res. 2009 Sep 1;15(17):5445-56
references.pmid: 19706799
references.citation: Cell. 1999 Feb 5;96(3):329-39
references.pmid: 10025399
references.citation: Science. 2003 Mar 14;299(5613):1753-5
references.pmid: 12637750
references.citation: Surg Oncol Clin N Am. 2001 Apr;10(2):289-312, viii
references.pmid: 11382588
references.citation: Mol Cell Biol. 1999 May;19(5):3278-88
references.pmid: 10207053
references.citation: Prostate. 2009 Jan 1;69(1):33-40
references.pmid: 18785179
references.citation: J Clin Invest. 2006 Apr;116(4):847-52
references.pmid: 16585951
references.citation: Science. 1999 Apr 30;284(5415):808-12
references.pmid: 10221914
references.citation: Endocr Relat Cancer. 2001 Sep;8(3):197-209
references.pmid: 11566611
references.citation: Mol Cell. 1998 Nov;2(5):559-69
references.pmid: 9844629
references.citation: Endocrinology. 2002 Sep;143(9):3259-67
references.pmid: 12193537
references.citation: Science. 1997 May 23;276(5316):1268-72
references.pmid: 9157888
references.citation: Cancer Res. 1972 Feb;32(2):226-32
references.pmid: 5058183
references.citation: Cancer Res. 1993 Aug 15;53(16):3736-40
references.pmid: 8339284
references.citation: Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S33-43
references.pmid: 17259557
references.citation: Endocr Rev. 2000 Jun;21(3):215-44
references.pmid: 10857553
references.citation: Endocr Rev. 2007 Feb;28(1):20-47
references.pmid: 16931767
references.citation: Nat Rev Cancer. 2008 Dec;8(12):915-28
references.pmid: 19029956
references.citation: Genes Cancer. 2010 Feb;1(2):125-41
references.pmid: 20975924
references.citation: J Biol Chem. 1999 Jan 1;274(1):305-15
references.pmid: 9867845
references.citation: Genesis. 2000 Feb;26(2):139-42
references.pmid: 10686610
references.citation: Arch Physiol Biochem. 2008 Feb;114(1):23-37
references.pmid: 18465356
references.citation: J Biol Chem. 2002 Oct 18;277(42):39684-95
references.pmid: 12138094
references.citation: Diabetologia. 1997 Jul;40 Suppl 2:S25-31
references.pmid: 9248698
references.citation: Am J Clin Nutr. 2007 Sep;86(3):s820-2
references.pmid: 18265475
references.citation: Cancer Cell. 2009 Mar 3;15(3):220-31
references.pmid: 19249680
references.citation: Mol Cancer Ther. 2007 Feb;6(2):607-17
references.pmid: 17308058
references.citation: Oncogene. 2010 Apr 29;29(17):2517-27
references.pmid: 20154728
references.citation: Mol Cancer Res. 2007 Feb;5(2):195-201
references.pmid: 17314276
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(23):9294-8
references.pmid: 2687878
references.citation: Mol Cancer Ther. 2009 Dec;8(12):3341-9
references.pmid: 19996272
references.citation: Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3650-7
references.pmid: 7731959
references.citation: Hum Pathol. 2003 Aug;34(8):803-8
references.pmid: 14506643
references.citation: Arch Physiol Biochem. 2008 Feb;114(1):63-70
references.pmid: 18465360
references.citation: Am J Clin Nutr. 2007 Sep;86(3):s836-42
references.pmid: 18265477
references.citation: Gastroenterology. 2004 Apr;126(4):1190-3
references.pmid: 15057757
references.citation: Cancer Res. 1992 Jul 15;52(14):3924-30
references.pmid: 1617668
references.citation: J Natl Cancer Inst. 1981 Jul;67(1):51-6
references.pmid: 6265682
references.citation: Cancer Cell. 2005 Oct;8(4):299-309
references.pmid: 16226705
references.citation: Cancer Res. 1998 Aug 1;58(15):3353-61
references.pmid: 9699666
references.citation: Nat Rev Cancer. 2004 Jul;4(7):505-18
references.pmid: 15229476
references.citation: Curr Pharm Des. 2007;13(7):671-86
references.pmid: 17346183
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2359-64
references.pmid: 19174523
references.citation: J Cell Sci. 1997 Sep;110 ( Pt 17):2089-97
references.pmid: 9378759
references.citation: Cancer Res. 2010 Jan 15;70(2):741-51
references.pmid: 20068149
references.citation: Nutr Metab Cardiovasc Dis. 2006 Jan;16(1):1-7
references.pmid: 16399485
references.citation: Cancer Cell. 2002 May;1(4):339-53
references.pmid: 12086849
references.citation: Clin Cancer Res. 2006 Sep 15;12(18):5277-87
references.pmid: 17000660
references.citation: J Clin Endocrinol Metab. 2002 Jan;87(1):245-54
references.pmid: 11788654
references.citation: EMBO J. 1986 Oct;5(10):2503-12
references.pmid: 2877871
references.citation: Cancer Res. 2007 Jan 1;67(1):391-7
references.pmid: 17210722
references.citation: Proc Natl Acad Sci U S A. 1976 Dec;73(12):4536-40
references.pmid: 1070004
references.citation: Biochem J. 1990 Sep 1;270(2):383-90
references.pmid: 1698059
references.citation: Oncogene. 2009 Aug 27;28(34):3009-21
references.pmid: 19581933
references.citation: Nature. 1985 May 9-15;315(6015):115-22
references.pmid: 2986015
references.citation: Cancer Res. 2003 Dec 15;63(24):8912-21
references.pmid: 14695208
references.citation: Nature. 1994 Jun 2;369(6479):414-8
references.pmid: 7910953
references.citation: Mol Cancer Ther. 2006 Jan;5(1):114-20
references.pmid: 16432169
references.citation: Cold Spring Harb Symp Quant Biol. 1994;59:459-70
references.pmid: 7587100
references.citation: Nature. 2009 Oct 8;461(7265):809-13
references.pmid: 19812674
references.citation: J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):381-406
references.pmid: 19016312
references.citation: Cancer Res. 2009 Mar 15;69(6):2443-52
references.pmid: 19258511
references.citation: Mol Cancer Ther. 2009 Aug;8(8):2110-21
references.pmid: 19671761
references.citation: Cancer Res. 2001 Sep 15;61(18):6747-54
references.pmid: 11559546
references.citation: J Natl Cancer Inst. 2007 Dec 5;99(23):1793-800
references.pmid: 18042933
references.citation: Int J Cancer. 2003 Dec 20;107(6):873-7
references.pmid: 14601044
references.citation: Cancer Res. 2009 Jan 1;69(1):161-70
references.pmid: 19117999