AZ1366: An Inhibitor of Tankyrase and the Canonical Wnt Pathway that Limits the Persistence of Non-Small Cell Lung Cancer Cells Following EGFR Inhibition.
Purpose:The emergence of EGFR inhibitors such as gefitinib, erlotinib, and osimertinib has provided novel treatment opportunities in EGFR-driven non-small cell lung cancer (NSCLC). However, most patients with EGFR-driven cancers treated with these inhibitors eventually relapse. Recent efforts have identified the canonical Wnt pathway as a mechanism of protection from EGFR inhibition and that inhibiting tankyrase, a key player in this pathway, is a potential therapeutic strategy for the treatment of EGFR-driven tumors.Experimental Design:We performed a preclinical evaluation of tankyrase inhibitor AZ1366 in combination with multiple EGFR-inhibitors across NSCLC lines, characterizing its antitumor activity, impingement on canonical Wnt signaling, and effects on gene expression. We performed pharmacokinetic and pharmacodynamic profiling of AZ1366 in mice and evaluated its therapeutic activity in an orthotopic NSCLC model.Results:In combination with EGFR inhibitors, AZ1366 synergistically suppressed proliferation of multiple NSCLC lines and amplified global transcriptional changes brought about by EGFR inhibition. Its ability to work synergistically with EGFR inhibition coincided with its ability to modulate the canonical Wnt pathway. Pharmacokinetic and pharmacodynamic profiling of AZ1366-treated orthotopic tumors demonstrated clinically relevant serum drug levels and intratumoral target inhibition. Finally, coadministration of an EGFR inhibitor and AZ1366 provided better tumor control and improved survival for Wnt-responsive lung cancers in an orthotopic mouse model.Conclusions:Tankyrase inhibition is a potent route of tumor control in EGFR-dependent NSCLC with confirmed dependence on canonical Wnt signaling. These data strongly support further evaluation of tankyrase inhibition as a cotreatment strategy with EGFR inhibition in an identifiable subset of EGFR-driven NSCLC.Clin Cancer Res; 23(6); 1531-41. ©2016 AACR.
Department of Biochemistry and Molecular Genetics.
Hannah A
HA
Scarborough
Division of Medical Oncology, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado.
Barbara A
BA
Helfrich
Department of Biochemistry and Molecular Genetics.
Matias
M
Casás-Selves
AstraZeneca R&D, Boston, Massachusetts.
Alwin G
AG
Schuller
AstraZeneca R&D, Boston, Massachusetts.
Shaun E
SE
Grosskurth
Division of Medical Oncology, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado.
Jihye
J
Kim
Division of Medical Oncology, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado.
Aik-Choon
AC
Tan
Division of Medical Oncology, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado.
Daniel C
DC
Chan
Division of Medical Oncology, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado.
Zhiyong
Z
Zhang
Department of Biochemistry and Molecular Genetics.
Vadym
V
Zaberezhnyy
Division of Medical Oncology, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado.
Paul A
PA
Bunn
Department of Biochemistry and Molecular Genetics. james.degregori@ucdenver.edu.
James
J
DeGregori
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D011799:Quinazolines; D038501:Tankyrases; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
Dev Cell. 2009 Jul;17(1):9-26
19619488
Nat Rev Cancer. 2010 Nov;10(11):760-74
20966921
Adv Enzyme Regul. 1984;22:27-55
6382953
PLoS One. 2010 Feb 23;5(2):e9370
20186325
Am J Pathol. 2001 Mar;158(3):987-96
11238046
PLoS Med. 2005 Mar;2(3):e73
15737014
Cancer Res. 1998 Apr 1;58(7):1344-7
9537226
Cancer Res. 2014 Jun 15;74(12):3294-305
24747911
N Engl J Med. 2009 Sep 3;361(10):947-57
19692680
Nat Genet. 2000 Mar;24(3):245-50
10700176
Cancer Discov. 2014 Sep;4(9):1046-61
24893891
Int J Mol Sci. 2014 Jul 08;15(7):12094-106
25007066
Cell. 2012 Jun 8;149(6):1245-56
22682247
Br J Cancer. 2001 Jul 6;85(1):64-8
11437403
Nature. 2009 Oct 1;461(7264):614-20
19759537
CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
22237781
Nat Biotechnol. 2012 Feb 19;30(3):283-8
22343925
Science. 1997 Mar 21;275(5307):1787-90
9065402
J Clin Invest. 2007 Oct;117(10):2740-50
17909619
J Thorac Oncol. 2014 Aug;9(8):1180-6
25157771
N Engl J Med. 2015 Apr 30;372(18):1689-99
25923549
Oncogene. 2006 Jun 26;25(27):3787-800
16799620
J Biol Chem. 2007 Aug 3;282(31):22662-7
17561506
Cancer Res. 2012 Aug 15;72(16):4154-64
22738915
PLoS One. 2015 Apr 02;10(4):e0124149
25835728
Genes Chromosomes Cancer. 2001 Mar;30(3):316-21
11170292
PLoS One. 2012;7(11):e48670
23144924
Cancer Res. 2012 Jun 1;72(11):2822-32
22440753
Cell Rep. 2015 Oct 20;13(3):524-532
26456820
Cancer Res. 2014 Oct 15;74(20):5891-902
25164010
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20932-7
18093943
BMC Cancer. 2013 Apr 28;13:211
23621985
J Clin Oncol. 2008 May 20;26(15):2442-9
18458038
J Med Chem. 2013 Feb 14;56(3):1341-5
23316926
J Natl Cancer Inst. 2009 Apr 15;101(8):548-50
19351922
Cancer Res. 1998 Mar 1;58(5):896-9
9500446
Nat Med. 2012 Jun;18(6):892-901
22610277
Am J Clin Pathol. 2006 Apr;125(4):534-41
16627264
Nat Med. 2016 Mar;22(3):262-9
26828195
Nat Chem Biol. 2009 Feb;5(2):100-7
19125156
Sci Transl Med. 2011 Mar 23;3(75):75ra26
21430269
Cancer Res. 2013 May 15;73(10):3132-44
23539443
Clin Cancer Res. 2016 Feb 1;22(3):644-56
26224873
Nat Rev Drug Discov. 2006 Dec;5(12):997-1014
17139285
J Clin Oncol. 2007 Jun 20;25(18):2504-5
17577025
Science. 2004 Apr 2;304(5667):97-100
15064417
ACS Med Chem Lett. 2015 Jan 13;6(3):254-9
25815142
Nat Rev Drug Discov. 2012 Dec;11(12):923-36
23197039
Oncol Rep. 2008 Jan;19(1):203-9
18097596