Differentiation Therapy Targeting the β-Catenin/CBP Interaction in Pancreatic Cancer
Open accessAbstract
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.
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Several compounds have been selected as inhibitors targeting β-catenin PPI, including small molecules such as ICG-001, NLs-StAx-h, and CRT inhibitors (iCRT3, iCRT5, iCRT14), Henryin, PKF115-584 and CGP049090.
“In addition, several compounds have been selected as inhibitors targeting β-cateninde PPI, including small molecules such as ICG-001 (176),448 NLs-StAx-h (177)449 and CRT inhibitors (iCRT3 (178), iCRT5 (179), iCRT14 (180)),450 Henryin (181),451 PKF115-584 (182) and CGP049090 (183).452”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [448]
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References 53 · Cited by 51
- Authors
- Manegold, P., Lai, K., Wu, Y., Teo, J.-L., Lenz, H.-J., Genyk, Y., Pandol, S., Wu, K., Lin, D., Chen, Y., Nguyen, C., Zhao, Y., & Kahn, M.
- Affiliations
- University of Southern California (US)
- City Of Hope National Medical Center (US)
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
- ORCID
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2018-03-29
- Volume
- 10
- Issue
- 4
- Pages
- 95
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC5923350
- OpenAlex
- W2794656614
- Cited by
- 51
- References
- 53
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 10
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (MA4403/1-1)
- National Institutes of Health (K08AA025112, U01DK108314, P30CA014089, R01CA166161, R21NS074392, R21AI105057, R01HL112638)
- Wright Foundation
- STOP CANCER
- American Cancer Society (IRG-58-007-54)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- pancreatic ductal adenocarcinoma, β-catenin, CBP, P300, Wnt signaling, KRAS, ICG-001, differentiation therapy, gemcitabine resistance, let-7a microRNA, survivin, cancer stem cells, patient-derived xenografts
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