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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI191370

Oncogenic KRAS/ERK/JUNB signaling suppresses differentiation regulator GATA6 in pancreatic cancer

Zheng Zhong,1 Xinang Cao,2 Pei-Ju Liao,1 Raman Sethi,3 Jeffrey A. Klomp,4 Clint A. Stalnecker,4 Jinmiao Chen,1 Yue Wan,2 Channing J. Der,4 and David M. Virshup1

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Zhong, Z. in: PubMed | Google Scholar |

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Cao, X. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Liao, P. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Sethi, R. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Klomp, J. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Stalnecker, C. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Chen, J. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Wan, Y. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Der, C. in: PubMed | Google Scholar

1Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

2Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

3Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore

4Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

Find articles by Virshup, D. in: PubMed | Google Scholar |

Published December 2, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI191370.
Copyright © 2025, Zhong et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 2, 2025 - Version history
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Abstract

GATA6 is a master regulator of differentiation in the pancreas and its expression levels determine the two main molecular subtypes of pancreatic cancer. High GATA6 contributes to the “classical” pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why GATA6 expression varies across pancreatic cancers and what regulate GATA6 expression remain elusive. Here we report that the oncogenic KRAS-activated ERK signaling suppresses GATA6 transcription in pancreatic cancers. GATA6 mRNA levels inversely correlated with KRAS/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a GATA6-EGFP reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for GATA6. Active ERK stabilizes JUNB protein while KRAS/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of GATA6. Up-regulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells and KRAS/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS/ERK signaling suppresses GATA6 to cause dedifferentiation in pancreatic cancer. Combining KRAS/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.

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graphical abstract
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Version history
  • Version 1 (December 2, 2025): In-Press Preview
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