Combined blockade of Src kinase and epidermal growth factor receptor with gemcitabine overcomes STAT3-mediated resistance of inhibition of pancreatic tumor growth.
OBJECTIVE
We previously established a mechanistic rationale for Src inhibition as a novel therapeutic target in pancreatic cancer and have identified activated STAT3 as a potential biomarker of resistance to Src inhibition. The purpose of this study was to translate the current understanding of complementary activated tyrosine kinase signaling pathways by targeting Src kinase and epidermal growth factor receptor (EGFR).


METHODS
IC(50) values for dasatinib, a Src kinase inhibitor, erlotinib, an EGFR tyrosine kinase inhibitor and gemcitabine were determined and sensitive and resistant pancreatic cancer cell lines were identified. The in vitro and in vivo effects of these agents on multiple signaling pathways and tumorigenicity in pancreatic cancer were investigated.


RESULTS
The combination of dasatinib, erlotinib, and gemcitabine resulted in cooperative inhibition of cell migration and invasion of both sensitive and resistant pancreatic cancer cells as well as cooperative inhibition of multiple signaling pathways including FAK, AKT, ERK, JNK, MAPK, and STAT3 at concentrations that were ineffective as individual agents or as double combinations of agents. The triple combination of agents was also most effective at inhibiting the growth of xenografts of both sensitive and resistant pancreatic cancer cells in vivo without increasing toxicity. Furthermore, combined inhibition of Src and EGFR with gemcitabine inhibited constitutively activated STAT3 in vitro and in vivo.


CONCLUSIONS
These results provide evidence that combined targeted biological therapy in addition to cytotoxic chemotherapy can overcome treatment resistance. Such treatment strategies may be used to tailor therapy based on identified biomarkers of resistance to targeted monotherapy.
Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Nagathihalli S
NS
Nagaraj
M Kay
MK
Washington
Nipun B
NB
Merchant
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000069439:Dasatinib; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D013844:Thiazoles; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019061:src-Family Kinases; D000069439:Dasatinib; D000093542:Gemcitabine
Adv Cancer Res. 1999;76:61-119
10218099
Oncogene. 2004 Oct 18;23(48):7957-68
15489913
Anticancer Res. 1993 May-Jun;13(3):565-9
8317885
J Clin Invest. 1992 Oct;90(4):1352-60
1401070
Cancer Res. 2009 May 1;69(9):3842-9
19383922
Oncologist. 2009 Jul;14(7):667-78
19581523
Mol Carcinog. 1998 Apr;21(4):261-72
9585256
Mol Cancer Ther. 2008 Jun;7(6):1708-19
18566242
J Clin Oncol. 2008 Jul 1;26(19):3204-12
18541900
Clin Cancer Res. 2009 Nov 15;15(22):6852-61
19861436
Clin Cancer Res. 2004 Apr 1;10(7):2307-18
15073106
Clin Cancer Res. 2009 Jun 15;15(12):4138-46
19509160
Mol Cancer Ther. 2010 Aug;9(8):2322-32
20682659
J Pharmacol Exp Ther. 2010 May;333(2):373-81
20100905
Science. 2008 Sep 26;321(5897):1801-6
18772397
Mol Cancer Res. 2007 Mar;5(3):203-20
17374728
Am J Pathol. 2006 Mar;168(3):962-72
16507911
Clin Cancer Res. 2004 Dec 1;10(23):8028-36
15585638
Pancreas. 2004 Jul;29(1):e1-8
15211117
Biochem Biophys Res Commun. 1998 Feb 13;243(2):503-8
9480838
J Biol Chem. 1995 Jun 30;270(26):15591-7
7797556
Cancer Cell. 2004 Sep;6(3):209-14
15380511
J Am Coll Surg. 2004 Jun;198(6):953-9
15194078
Cancer Res. 2002 May 1;62(9):2699-707
11980671
Cancer Treat Rev. 2009 Jun;35(4):335-9
19131170
Clin Cancer Res. 2008 Feb 15;14(4):1182-91
18281553
Clin Pharmacol Ther. 2006 Aug;80(2):136-45
16890575
Biochim Biophys Acta. 1996 Jun 7;1287(2-3):121-49
8672527
CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
18287387
Oncogene. 2008 Dec 4;27(57):7212-22
18794807
Oncogene. 2003 Jul 3;22(27):4150-65
12833138