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Cited by 153

The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.

Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis

Kim, Michael P., Li, Xinqun, Deng, Jenying, Zhang, Yun, Dai, Bingbing, Allton, Kendra L., Hughes, Tara G., Siangco, Christian, Augustine, Jithesh J., Kang, Ya'an, McDaniel, Joy M., Xiong, Shunbin, Koay, Eugene J., McAllister, Florencia, Bristow, Christopher A., Heffernan, Timothy P., Maitra, Anirban, Liu, Bin, Barton, Michelle C., Wasylishen, Amanda R., Fleming, Jason B., Lozano, Guillermina·2021·Cancer Discovery
DOI 10.1158/2159-8290.cd-20-1228

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis. Significance: Oncogenic KRAS and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic KRAS effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis. This article is highlighted in the In This Issue feature, p. 1861

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Research works printed but not linked: 34

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Metadata

Authors
Kim, M. P., Li, X., Deng, J., Zhang, Y., Dai, B., Allton, K. L., Hughes, T. G., Siangco, C., Augustine, J. J., Kang, Y., McDaniel, J. M., Xiong, S., Koay, E. J., McAllister, F., Bristow, C. A., Heffernan, T. P., Maitra, A., Liu, B., Barton, M. C., Wasylishen, A. R., Fleming, J. B., & Lozano, G.
Affiliations
  • 1Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3Department of Pharmaceutical Sciences, Texas Southern University, Houston, Texas.
  • 4Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 5Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 8Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 9Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 10Division of Oncological Sciences, Oregon Health and Science University School of Medicine, Portland, Oregon.
  • 11Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2021-04-10
Volume
11
Issue
8
Pages
2094-2111
ISSN
  • 2159-8274
  • 2159-8290
DOI
10.1158/2159-8290.cd-20-1228
Cited by
153
References
8
Language
en
Funders
  • NIH NCI (K08CA218690, R01CA82577, R01CA220236)
  • NIH (P01CA117969, T32 CA 009599, 1S10OD024976-01)
  • CPRIT (RP17002)
  • Cancer Center Support (P30CA016672)

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CoChat. (2026). Citation check: Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis. https://app.cochat.ai/papers/10.1158/2159-8290.cd-20-1228
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Kim, M. P., Li, X., Deng, J., Zhang, Y., Dai, B., Allton, K. L., Hughes, T. G., Siangco, C., Augustine, J. J., Kang, Y., McDaniel, J. M., Xiong, S., Koay, E. J., McAllister, F., Bristow, C. A., Heffernan, T. P., Maitra, A., Liu, B., Barton, M. C., . . . Lozano, G. (2021). Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-20-1228

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

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