title: The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies. Cancer stem cells (CSCs), which are not targeted by current therapies, may be the reason for pronounced therapy resistance. A new treatment option in phase II trials is cabozantinib that inhibits the pancreatic CSC surface marker and tyrosine kinase receptor c-Met. The purpose of this study was to evaluate the effect of cabozantinib to stem-like features and therapy resistance. Established PDA cell lines, a gemcitabine-resistant subclone, non-malignant pancreatic ductal cells and primary spheroidal cultures from patient tumors were analyzed by MTT-assay, flow cytometry, colony and spheroid formation assays, western blotting, qRT-PCR, antibody protein array, immunohistochemistry and morphological features. Cabozantinib inhibited viability and spheroid formation and induced apoptosis in malignant cells with minor effects in non-malignant cells. After long-term cabozantinib treatment, PDA cells had altered anti- and pro-apoptotic signaling, but still responded to cabozantinib, as apoptosis only slightly decreased and viability only slightly increased suggesting a low resistance-inducing potential of cabozantinib. In parallel, c-Met expression and the pluripotency transcription factor SOX2 were downregulated, which might counteract development of full therapy resistance in long-term treated subclones. In single-treatment studies, cabozantinib increased efficacy of gemcitabine. Most importantly, cabozantinib strongly induced apoptosis and reduced viability in PDA cell lines, which are completely resistant toward gemcitabine. In primary, CSC-enriched spheroidal cultures cabozantinib downregulated CSC markers SOX2, c-Met and CD133 and induced apoptosis. These findings suggest that the clinical use of cabozantinib may be more effective than current chemotherapeutics.
authors: Department of Experimental Medicine, Molecular OncoSurgery Group, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany.
authors: C
authors: C
authors: Hage
authors: V
authors: V
authors: Rausch
authors: N
authors: N
authors: Giese
authors: T
authors: T
authors: Giese
authors: F
authors: F
authors: Schönsiegel
authors: S
authors: S
authors: Labsch
authors: C
authors: C
authors: Nwaeburu
authors: J
authors: J
authors: Mattern
authors: J
authors: J
authors: Gladkich
authors: I
authors: I
authors: Herr
mesh_terms: D000813:Anilides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000813:Anilides; D011725:Pyridines; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D003841:Deoxycytidine; C558660:cabozantinib; D019859:Proto-Oncogene Proteins c-met; D000093542:Gemcitabine
references: J Immunol Methods. 1991 Jun 3;139(2):271-9
references: 1710634
references: Nature. 2009 Jul 2;460(7251):118-22
references: 19571885
references: J Pathol. 2012 Jul;227(3):325-35
references: 22262369
references: Stem Cells. 2011 Jun;29(6):883-7
references: 21509907
references: Nat Rev Cancer. 2012 Jan 24;12(2):89-103
references: 22270953
references: N Engl J Med. 2011 May 12;364(19):1817-25
references: 21561347
references: Nature. 2004 Nov 18;432(7015):396-401
references: 15549107
references: Nature. 2009 Aug 27;460(7259):1085-6
references: 19713919
references: Pancreatology. 2004;4(6):567-86
references: 15550766
references: Nature. 2006 Aug 17;442(7104):742-3
references: 16915262
references: Br J Cancer. 2013 Jan 15;108(1):1-8
references: 23299539
references: Cell. 2007 Nov 30;131(5):861-72
references: 18035408
references: Genes Dev. 2012 Sep 15;26(18):1997-2000
references: 22987633
references: Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9951-6
references: 21628563
references: Cancer Res. 2007 Feb 1;67(3):1030-7
references: 17283135
references: Clin Cancer Res. 2008 Sep 15;14(18):5646-8
references: 18794070
references: Cancer Res. 2010 Mar 1;70(5):2115-25
references: 20160041
references: Cancer Res. 2011 Jul 15;71(14):4758-68
references: 21613405
references: JOP. 2011 Mar 09;12(2):96-100
references: 21386629
references: Gastroenterology. 2011 Dec;141(6):2218-2227.e5
references: 21864475
references: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8
references: 12629218
references: Cell Stem Cell. 2007 Sep 13;1(3):313-23
references: 18371365
references: Cancer Res. 2010 Jun 15;70(12):5004-13
references: 20530687
references: Nature. 1994 Feb 17;367(6464):645-8
references: 7509044
references: Diabetes. 2004 Aug;53(8):2143-52
references: 15277399
references: Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
references: 14685170
references: Cancer Res. 1975 Oct;35(10):2619-30
references: 1098765
references: Gastroenterology. 2007 Feb;132(2):720-32
references: 17258722
references: Gut. 2009 Jul;58(7):949-63
references: 18829980
references: Cell Stem Cell. 2011 Nov 4;9(5):433-46
references: 22056140