title: Small molecule tyrosine kinase inhibitors in pancreatic cancer.
abstract: Pancreatic cancer has proven to be chemo-resistant, with gemcitabine being the only cytotoxic agent approved for advanced pancreatic cancer since 1996. Tyrosine kinase inhibitors represent a newer generation of chemotherapeutic agents targeting specific tumor pathways associated with carcinogenesis including cell cycle control, signal transduction, apoptosis and angiogenesis. These agents present a more selective way of treating pancreatic cancer. Erlotinib is the prototype of the tyrosine kinase inhibitors with proven efficacy in advanced pancreatic cancer and has been recently approved in that setting. Multiple other tyrosine kinase inhibitors targeting the VEGFR, PDGFR, and Src kinases are in various phases of clinical trials testing. The preliminary results of these trials have been disappointing. Current challenges in pancreatic cancer clinical trials testing include improving patient selection, identifying effective combinations, improving the predictive value of current preclinical models and better study designs. This review summarizes the present clinical development of tyrosine kinase inhibitors in pancreatic cancer and strategies for future drug development.
authors.affiliation: Department of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University, MI, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Gupta
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
references.citation: Ann Surg. 2002 Dec;236(6):738-49; discussion 749
references.pmid: 12454512
references.citation: Anticancer Res. 1993 May-Jun;13(3):565-9
references.pmid: 8317885
references.citation: Physiol Rev. 1999 Oct;79(4):1283-316
references.pmid: 10508235
references.citation: Semin Oncol. 2003 Feb;30(1 Suppl 1):3-11
references.pmid: 12644979
references.citation: Curr Opin Oncol. 1998 Jul;10(4):362-6
references.pmid: 9702405
references.citation: Cancer Res. 2002 Oct 1;62(19):5476-84
references.pmid: 12359756
references.citation: Cancer Metastasis Rev. 2003 Dec;22(4):337-58
references.pmid: 12884910
references.citation: J Clin Oncol. 1997 Jun;15(6):2403-13
references.pmid: 9196156
references.citation: Cancer Lett. 2006 Feb 28;233(2):328-37
references.pmid: 15893416
references.citation: CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
references.pmid: 17237035
references.citation: Am J Pathol. 2004 Jul;165(1):35-52
references.pmid: 15215160
references.citation: J Clin Invest. 2003 May;111(9):1287-95
references.pmid: 12727920
references.citation: Lancet. 2008 Jun 21;371(9630):2101-8
references.pmid: 18514303
references.citation: Lancet Oncol. 2008 Feb;9(2):132-8
references.pmid: 18249033
references.citation: EMBO J. 2000 Jul 3;19(13):3159-67
references.pmid: 10880430
references.citation: J Clin Oncol. 2004 Sep 15;22(18):3776-83
references.pmid: 15365074
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):144-51
references.pmid: 16397036
references.citation: Annu Rev Cell Dev Biol. 1997;13:513-609
references.pmid: 9442882
references.citation: Pancreas. 2002 Aug;25(2):122-9
references.pmid: 12142733
references.citation: J Clin Oncol. 2010 Aug 1;28(22):3605-10
references.pmid: 20606093
references.citation: J Clin Oncol. 2005 Feb 10;23(5):1011-27
references.pmid: 15585754
references.citation: J Clin Oncol. 2001 Sep 15;19(18 Suppl):32S-40S
references.pmid: 11560969
references.citation: Int J Oncol. 2004 Jul;25(1):203-10
references.pmid: 15202007
references.citation: Int J Clin Oncol. 2001 Apr;6(2):59-65
references.pmid: 11706751
references.citation: J Clin Oncol. 2003 Jul 15;21(14):2787-99
references.pmid: 12860957
references.citation: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references.pmid: 11252954
references.citation: J Clin Oncol. 2007 May 20;25(15):1960-6
references.pmid: 17452677
references.citation: Semin Oncol. 2006 Aug;33(4):369-85
references.pmid: 16890793
references.citation: Int J Cancer. 2000 Jan 1;85(1):27-34
references.pmid: 10585578
references.citation: Br J Surg. 1995 Jan;82(1):111-5
references.pmid: 7881926
references.citation: J Pathol. 1992 Jan;166(1):7-12
references.pmid: 1538276
references.citation: Drug Resist Updat. 2006 Feb-Apr;9(1-2):1-18
references.pmid: 16621676
references.citation: Cancer Res. 2000 Apr 15;60(8):2178-89
references.pmid: 10786682
references.citation: Cancer Res. 2005 Nov 15;65(22):10371-80
references.pmid: 16288027
references.citation: Clin Cancer Res. 2003 Dec 15;9(17):6534-44
references.pmid: 14695158
references.citation: J Clin Oncol. 2005 Aug 20;23(24):5474-83
references.pmid: 16027439
references.citation: Cell. 2000 Oct 13;103(2):211-25
references.pmid: 11057895
references.citation: Clin Adv Hematol Oncol. 2003 Jul;1(7):430-4
references.pmid: 16258429
references.citation: Br J Cancer. 1999 Mar;79(9-10):1553-63
references.pmid: 10188906
references.citation: Pharmacol Ther. 1999 May-Jun;82(2-3):231-9
references.pmid: 10454200
references.citation: Cell. 2006 Jun 16;125(6):1029-31
references.pmid: 16777592
references.citation: Cytokine Growth Factor Rev. 2004 Aug;15(4):275-86
references.pmid: 15207817
references.citation: Int J Cancer. 2001 May 1;92(3):361-9
references.pmid: 11291072
references.citation: Adv Cancer Res. 2000;79:1-38
references.pmid: 10818676
references.citation: J Mol Med (Berl). 1999 Jul;77(7):527-43
references.pmid: 10494799
references.citation: Int J Cancer. 2002 Nov 10;102(2):101-8
references.pmid: 12385004
references.citation: N Engl J Med. 1971 Nov 18;285(21):1182-6
references.pmid: 4938153
references.citation: Am J Clin Oncol. 2005 Dec;28(6):570-5
references.pmid: 16317266
references.citation: J Clin Oncol. 2005 May 20;23(15):3509-16
references.pmid: 15908661
references.citation: Int J Cancer. 1995 Sep 4;62(5):529-35
references.pmid: 7665222
references.citation: J Clin Oncol. 2002 Nov 1;20(21):4368-80
references.pmid: 12409337
references.citation: Anticancer Drugs. 2007 Jun;18(5):569-79
references.pmid: 17414626
references.citation: Semin Oncol. 2006 Dec;33(6 Suppl 11):S10-3
references.pmid: 17178279
references.citation: Science. 1995 Mar 24;267(5205):1782-8
references.pmid: 7892601
references.citation: Clin Cancer Res. 2003 Apr;9(4):1546-56
references.pmid: 12684431
references.citation: Cancer Invest. 2007 Oct;25(7):647-57
references.pmid: 18027154
references.citation: Anticancer Res. 1998 Nov-Dec;18(6B):4613-9
references.pmid: 9891528
references.citation: JAMA. 2007 Jan 17;297(3):267-77
references.pmid: 17227978
references.citation: Cancer Res. 2004 Oct 1;64(19):7099-109
references.pmid: 15466206