ArticleOncogene2021
Loss of the wild-type KRAS allele promotes pancreatic cancer progression through functional activation of YAP1.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 26 citations in OpenAlex.
- A HRH1-YAP1 feedback loop drives pancreatic cancer progression and predicts therapeutic response.Oncology letters · 2026Article
- Article
- Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Proteomic Perspectives on KRAS-Driven Cancers and Emerging Therapeutic Approaches.Current oncology (Toronto, Ont.) · 2025Review
- A first-in-class EGFR-directed KRAS G12V selective inhibitor.Cancer cell · 2025Article
- KRAS: the Achilles' heel of pancreas cancer biology.The Journal of clinical investigation · 2025Review
- The Hippo signaling pathway modulates pancreatic tissue homeostasis.Cell death discovery · 2025Review
- Unlocking the Genetic Secrets of Pancreatic Cancer:Cancers · 2025Review
- Article
- KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition.Cancer research · 2025Article
- Characteristics ofTherapeutic advances in medical oncology · 2025Article
- Rac1 GTPase Regulates the βTrCP-Mediated Proteolysis of YAP Independently of the LATS1/2 Kinases.Cancers · 2024Article
- Complex interplay between RAS GTPases and RASSF effectors regulates subcellular localization of YAP.EMBO reports · 2024Article
- A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia.EMBO reports · 2024Article
- KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo.Nature communications · 2024Article
- Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia.The Journal of clinical investigation · 2023Article
- KRAS-Dependency in Pancreatic Ductal Adenocarcinoma: Mechanisms of Escaping in Resistance to KRAS Inhibitors and Perspectives of Therapy.International journal of molecular sciences · 2023Review
- TEAD Inhibitors Sensitize KRASPharmaceuticals (Basel, Switzerland) · 2023Article
- The RNA-Binding Protein HuR Posttranscriptionally Regulates the Protumorigenic Activator YAP1 in Pancreatic Ductal Adenocarcinoma.Molecular and cellular biology · 2022Article
- Non-genetic adaptive resistance to KRASFrontiers in oncology · 2022Review
Corrections and comments
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
Human pancreatic ductal adenocarcinoma (PDAC) harboring one KRAS mutant allele often displays increasing genomic loss of the remaining wild-type (WT) allele (known as LOH at KRAS) as tumors progress to metastasis, yet the molecular ramification of this WT allelic loss is unknown. In this study, we showed that the restoration of WT KRAS expression in human PDAC cell lines with LOH at KRAS significantly attenuated the malignancy of PDAC cells both in vitro and in vivo, demonstrating a tumor-suppressive role of the WT KRAS allele. Through RNA-Seq, we identified the HIPPO signaling pathway to be positively regulated by WT KRAS in PDAC cells. In accordance with this observation, PDAC cells with LOH at KRAS exhibited increased nuclear localization and activation of transcriptional co-activator YAP1. Mechanistically, we discovered that WT KRAS expression sequestered YAP1 from the nucleus, through enhanced 14-3-3zeta interaction with phosphorylated YAP1 at S127. Consistently, expression of a constitutively-active YAP1 mutant in PDAC cells bypassed the growth inhibitory effects of WT KRAS. In patient samples, we found that the YAP1-activation genes were significantly upregulated in tumors with LOH at KRAS, and YAP1 nuclear localization predicted poor survival for PDAC patients. Collectively, our results reveal that the WT allelic loss leads to functional activation of YAP1 and enhanced tumor malignancy, which explains the selection advantage of the tumor cells with LOH at KRAS during pancreatic cancer clonal evolution and progression to metastasis, and should be taken into consideration in future therapeutic strategies targeting KRAS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.