The DOI matches its Crossref record; 58 of the 59 references it cites were found in a registry or an index.
Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer
Open accessAbstract
Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible Kras(G12D)-driven mouse model of PDAC has established a critical role for sustained Kras(G12D) expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of Kras(G12D)-independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving Kras(G12D)-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.
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In the citing paper
“Previous studies have demonstrated that activated Yap, through genetic amplification of YAP- or WNT5a-mediated dysregulation of the Hippo pathway, enables bypass of Kras suppression in Kras-driven murine pancreatic cancer and lung cancer models (37–39).”
From YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis (2024) · cites this paper as [38]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Prior studies using inducible suppression of KRAS via RNA interference or genetically engineered inducible KrasG12D alleles (i.e., “iKras” model) have suggested that amplification of YAP1 or induction of an epithelial-to-mesenchymal transition (EMT) can confer a state of RAS independence and overcome KRASG12D suppression (35–38).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [36]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We had previously identified YAP1 activation, through either gene amplification or activation of a non-canonical WNT pathway, as a major driver for bypassing KRAS dependency in PDAC.9,11”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Using a genetically engineered mouse (GEM) model of PDAC driven by inducible KRASG12D, we recently demonstrated that activation of the YAP1 oncogene drives resistance to genetic inactivation of KRAS∗, a finding further confirmed in KRAS∗-driven colorectal cancer (CRC).”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The YAP1 oncogene has been well established as one of the major drivers of bypassing oncogene addiction and promoting acquired resistance to targeted therapies in several cancer types, including pancreatic cancer, lung cancer, colorectal cancer, melanoma, and glioblastoma.9,10,38,39,40”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [9]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Similarly, it has long been known that YAP/TAZ interact with oncogenic KRAS-mediated signaling and modulate the response to KRAS inhibition.”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [103]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“A mesenchymal-like differentiation state can act as a resistance mechanism to KRAS inhibitors [126,128,130].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [130]
The cited source says what the claim attributes to it.
In the citing paper
“An early study of a PDAC mouse model showed that inactivation of KRAS G12D led to spontaneous tumor relapse [103].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [103]
The cited source says what the claim attributes to it.
In the citing paper
“YAP1 amplification and YAP1/TEAD2 signaling enabled relapsed tumors to bypass oncogenic KRAS addiction for tumor maintenance [103].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [103]
The cited source says what the claim attributes to it.
In the citing paper
“Similarly, our previous work using an inducible KrasG12D-driven PDAC model demonstrated spontaneous tumor relapse in the majority of animals following genetic extinction of KrasG12D.9”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [9]
In the citing paper
“In the context of pancreatic cancer, KRAS dependency can be by-passed by the elevated expression of the transcription factor YAP1, which promotes EMT and confers cell-intrinsic resistance to KRAS loss (84, 85).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [85]
In the citing paper
“withdrawal of mutant Ras signaling in preclinical models that include loss of tumor suppressor function leads to tumors that can re-occur in a Ras-independent fashion67.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [67]
In the citing paper
“some KRAS-mutant cancer cells, including lung (20) and pancreatic cancer cells (21, 22), can survive in the absence of the KRAS oncogene.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [21]
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“[ 77 , 86 , 88 ] E R K - d e p e n d e n t n e g a t i v e f ee d b a c k E R K r e s t r a i n s S O S , R T K s a n d a d a p t o r p r o t e i n s t h r o u g h p h o s p h o r y l a - t i o n a n d S P R Y / D U S P i n d u c t i o n .”
Metadata
- Authors
- Kapoor, A., Yao, W., Ying, H., Hua, S., Liewen, A., Wang, Q., Zhong, Y., Wu, C.-J., Sadanandam, A., Hu, B., Chang, Q., Chu, G. C., Al-Khalil, R., Jiang, S., Xia, H., Fletcher-Sananikone, E., Lim, C., Horwitz, G. I., Viale, A., Pettazzoni, P., Sanchez, N., Wang, H., Protopopov, A., Zhang, J., Heffernan, T., Johnson, R. L., Chin, L., Wang, Y. A., Draetta, G., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Institute of Cancer Research (GB)
- Brigham and Women's Hospital (US)
- Corresponding author
- Ying, Haoqiang
- DePinho, Ronald A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 158
- Issue
- 1
- Pages
- 185-197
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4109295
- OpenAlex
- W2157912474
- Cited by
- 716
- References
- 59
- Citations by year
- 2026: 29 · 2025: 45 · 2024: 65 · 2023: 67 · 2022: 56 · 2021: 74 · 2020: 63 · 2019: 70 · 2018: 59 · 2017: 60 · 2016: 49 · 2015: 62 · 2014: 16
- FWCI
- 31.06
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-11-14)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute for Health and Care Research
- National Cancer Institute (CA-16672, U01CA084313, P30CA016672, P01CA117969)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK094865, R01DK102611)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- YAP, TEAD2, KRAS G12D, pancreatic ductal adenocarcinoma, tumor recurrence, MAPK signaling, E2F transcription factors, cell cycle, DNA replication, transcriptional coactivator
- MeSH terms
- YAP-Signaling Proteins, TEA Domain Transcription Factors, Adenocarcinoma, Animals, Cell Cycle, Disease Models, Animal, DNA Replication, DNA-Binding Proteins, Humans, Pancreatic Neoplasms, Phosphoproteins, Proto-Oncogene Proteins, Transcription Factors, Proto-Oncogene Proteins p21(ras), ras Proteins, Cell Cycle Proteins, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, E2F Transcription Factors, Mice
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