Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers-Reference-Cited by-同舟云学术

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Published:2024-06-07 Issue:6700 Volume:384 Page:
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Klomp Jeffrey A.¹²^ORCID,Klomp Jennifer E.¹^ORCID,Stalnecker Clint A.¹²^ORCID,Bryant Kirsten L.¹²^ORCID,Edwards A. Cole³,Drizyte-Miller Kristina¹^ORCID,Hibshman Priya S.³,Diehl J. Nathaniel⁴^ORCID,Lee Ye S.²^ORCID,Morales Alexis J.¹^ORCID,Taylor Khalilah E.¹^ORCID,Peng Sen⁵,Tran Nhan L.⁶,Herring Laura E.⁷^ORCID,Prevatte Alex W.⁷,Barker Natalie K.⁷^ORCID,Hover Laura D.⁸,Hallin Jill⁹^ORCID,Chowdhury Saikat¹⁰^ORCID,Coker Oluwadara¹⁰^ORCID,Lee Hey Min¹⁰^ORCID,Goodwin Craig M.¹^ORCID,Gautam Prson¹¹^ORCID,Olson Peter⁹^ORCID,Christensen James G.⁹^ORCID,Shen John P.¹⁰^ORCID,Kopetz Scott¹⁰^ORCID,Graves Lee M.¹²^ORCID,Lim Kian-Huat¹²^ORCID,Wang-Gillam Andrea¹²^ORCID,Wennerberg Krister¹¹¹³^ORCID,Cox Adrienne D.¹²³¹⁴^ORCID,Der Channing J.¹²³⁴^ORCID

Affiliation:

1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

2. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

3. Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

4. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

5. Illumina, Inc., San Diego, CA 92121, USA.

6. Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.

7. Michael Hooker Proteomics Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

8. Monoceros Biosystems LLC, San Diego, CA 92130, USA.

9. Mirati Therapeutics, Inc., San Diego, CA 92121, USA.

10. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

11. Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.

12. Division of Medical Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.

13. Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

14. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Abstract

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal–regulated kinase (ERK)–dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/science.adk0775

Reference106 articles.

1. The current state of the art and future trends in RAS-targeted cancer therapies

2. The pancreatic cancer genome revisited

3. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer

4. A Central Role for RAF→MEK→ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma

5. Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

Cited by 5 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer;Cancer Cell;2024-09

2. The KRAS mutational spectrum and its clinical implications in pancreatic cancer;Cancer Cell;2024-09

3. Reporter-based screening identifies RAS-RAF stabilizing mutations as drivers of resistance to broad-spectrum RAS inhibition in colorectal cancer;2024-07-03

4. Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer;Science;2024-06-07

5. Negative regulation of APC/C activation by MAPK-mediated attenuation of Cdc20^Slp1under stress;2024-04-03