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Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations
Open accessPublished version of a preprint
Abstract
Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patient-derived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status. Significance: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials. Cancer Discov; 4(8); 905–13. ©2014 AACR. See related commentary by Amaravadi and Debnath, p. 873 This article is highlighted in the In This Issue feature, p. 855
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“Autophagy is critical for cancer cell growth and tumorigenesis in mouse models of PDAC207–209”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [208]
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Metadata
- Authors
- Yang, A., Rajeshkumar, N. V., Wang, X., Yabuuchi, S., Alexander, B. M., Chu, G. C., Von Hoff, D. D., Maitra, A., & Kimmelman, A. C.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Johns Hopkins University (US)
- Brigham and Women's Hospital (US)
- 4Translational Genomics Research Institute, Phoenix, Arizona; Departments of
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kimmelman, Alec C.
- Venue
- Cancer Discovery
- Published
- 2014-08-01
- Volume
- 4
- Issue
- 8
- Pages
- 905-913
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC4125497
- OpenAlex
- W2148330792
- Cited by
- 486
- References
- 33
- Citations by year
- 2026: 16 · 2025: 32 · 2024: 28 · 2023: 34 · 2022: 47 · 2021: 61 · 2020: 44 · 2019: 43 · 2018: 41 · 2017: 45 · 2016: 37 · 2015: 43 · 2014: 15
- FWCI
- 35.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA127003, R01CA157490, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- autophagy, pancreatic ductal adenocarcinoma, p53 status, autophagy inhibition, hydroxychloroquine, KRAS-driven tumors, premalignant pancreatic lesions, tumor progression, patient-derived xenografts
- MeSH terms
- Animals, Autophagy, Cell Transformation, Neoplastic, Disease Models, Animal, Humans, Pancreatic Neoplasms, Tumor Suppressor Protein p53, Loss of Heterozygosity, Xenograft Model Antitumor Assays, Mice
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