Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer

Philipp Manegold; Keane K Y Lai; Yongfeng Wu; Jia-Ling Teo; Heinz-Josef Lenz; Yuri S Genyk; Stephen J Pandol; Kaijin Wu; David P Lin; Yibu Chen; Cu Nguyen; Yi Zhao; Michael Kahn

doi:10.3390/cancers10040095

Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer

Cancers (Basel). 2018 Mar 29;10(4):95. doi: 10.3390/cancers10040095.

Authors

Philipp Manegold^{1

2}, Keane K Y Lai^{3

4

5

6

7}, Yongfeng Wu^{8

9}, Jia-Ling Teo^{10

11

12}, Heinz-Josef Lenz^{13

14

15}, Yuri S Genyk¹⁶, Stephen J Pandol^{17

18}, Kaijin Wu^{19

20}, David P Lin²¹, Yibu Chen²², Cu Nguyen^{23

24

25}, Yi Zhao^{26

27

28}, Michael Kahn^{29

30

31

32

33

34}

Affiliations

¹ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. philipp.manegold@uniklinik-freiburg.de.
² Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. philipp.manegold@uniklinik-freiburg.de.
³ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. klai@coh.org.
⁴ Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA. klai@coh.org.
⁵ Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. klai@coh.org.
⁶ City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. klai@coh.org.
⁷ Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA. klai@coh.org.
⁸ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. wuyf001@163.com.
⁹ Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. wuyf001@163.com.
¹⁰ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. jteo@coh.org.
¹¹ Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. jteo@coh.org.
¹² Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. jteo@coh.org.
¹³ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. LENZ@med.usc.edu.
¹⁴ Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. LENZ@med.usc.edu.
¹⁵ Department of Medicine, University of Southern California, Los Angeles, CA 90033, USA. LENZ@med.usc.edu.
¹⁶ Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA. yuri.genyk@health.usc.edu.
¹⁷ Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA. Stephen.Pandol@cshs.org.
¹⁸ Pancreatic Research Program, Cedars-Sinai Medical Center, Veterans Affairs Greater Los Angeles Healthcare System, and Department of Medicine, University of California, Los Angeles, CA 90048, USA. Stephen.Pandol@cshs.org.
¹⁹ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. kaijinwu@usc.edu.
²⁰ Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. kaijinwu@usc.edu.
²¹ Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. dplin@hotmail.com.
²² Health Sciences Libraries, University of Southern California, Los Angeles, CA 90033, USA. yibuchen@usc.edu.
²³ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. cunguyen@coh.org.
²⁴ Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. cunguyen@coh.org.
²⁵ Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. cunguyen@coh.org.
²⁶ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. yizhao@usc.edu.
²⁷ Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. yizhao@usc.edu.
²⁸ Department of Medicine, University of Southern California, Los Angeles, CA 90033, USA. yizhao@usc.edu.
²⁹ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA. mkahn@coh.org.
³⁰ Center for Molecular Pathways and Drug Discovery, University of Southern California, Los Angeles, CA 90033, USA. mkahn@coh.org.
³¹ Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. mkahn@coh.org.
³² City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. mkahn@coh.org.
³³ Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA 90033, USA. mkahn@coh.org.
³⁴ Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles, CA 90033, USA. mkahn@coh.org.

Abstract

Background: Although canonical Wnt signaling is known to promote tumorigenesis in pancreatic ductal adenocarcinoma (PDAC), a cancer driven principally by mutant K-Ras, the detailed molecular mechanisms by which the Wnt effector β-catenin regulates such tumorigenesis are largely unknown. We have previously demonstrated that β-catenin's differential usage of the Kat3 transcriptional coactivator cyclic AMP-response element binding protein-binding protein (CBP) over its highly homologous coactivator p300 increases self-renewal and suppresses differentiation in other types of cancer.

Aim/methods: To investigate Wnt-mediated carcinogenesis in PDAC, we have used the specific small molecule CBP/β-catenin antagonist, ICG-001, which our lab identified and has extensively characterized, to examine its effects in human pancreatic cancer cells and in both an orthotopic mouse model and a human patient-derived xenograft (PDX) model of PDAC.

Results/conclusion: We report for the first time that K-Ras activation increases the CBP/β-catenin interaction in pancreatic cancer; and that ICG-001 specific antagonism of the CBP/β-catenin interaction sensitizes pancreatic cancer cells and tumors to gemcitabine treatment. These effects were associated with increases in the expression of let-7a microRNA; suppression of K-Ras and survivin; and the elimination of drug-resistant cancer stem/tumor-initiating cells.

Abstract

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