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Cited by 83Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer

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Klomp, Jennifer E., Diehl, J. Nathaniel, Klomp, Jeffrey A., Edwards, A. Cole, Yang, Runying, Morales, Alexis J., Taylor, Khalilah E., Drizyte-Miller, Kristina +16 more·2024·Science
DOI 10.1126/science.adk0850PMC PMC11301400
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Abstract

To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer. We established that ERK controls a highly dynamic and complex phosphoproteome that converges on cyclin-dependent kinase regulation and RAS homolog guanosine triphosphatase function (RHO GTPase). Our findings establish the most comprehensive molecular portrait and mechanisms by which ERK drives KRAS-dependent pancreatic cancer growth.

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  • Recent work characterizes complex and dynamic signaling changes following KRAS inhibition, particularly delayed emergence of adaptive and compensatory mechanisms that contribute to acquired resistance.

    “These findings are in line with recent work characterizing the complex and dynamic signaling changes following KRAS inhibition, particularly the delayed emergence of adaptive and compensatory mechanisms that contribute to acquired resistance.37”

    From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [37]

    The Discussion describes a highly dynamic response to KRAS–ERK inhibition, with delayed adaptive and compensatory activities. The time-course experiments in Results used ERK inhibition, and the Discussion says those activities *may* drive acquired resistance; the citing sentence presents their contribution to resistance as established following KRAS inhibition. (LLM, conf=0.85)

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Cited by

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Authors
Klomp, J. E., Diehl, J. N., Klomp, J. A., Edwards, A. C., Yang, R., Morales, A. J., Taylor, K. E., Drizyte-Miller, K., Bryant, K. L., Schaefer, A., Johnson, J. L., Huntsman, E. M., Yaron, T. M., Pierobon, M., Baldelli, E., Prevatte, A. W., Barker, N. K., Herring, L. E., Petricoin, E. F., Graves, L. M., Cantley, L. C., Cox, A. D., Der, C. J., & Stalnecker, C. A.
Affiliations
  • University of North Carolina at Chapel Hill (US)
  • Lineberger Comprehensive Cancer Center; University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Harvard University (US)
  • Weill Cornell Medicine (US)
  • George Mason University (US)
Corresponding author
  • Der, Channing J.
  • Stalnecker, Clint A.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-06-07
Volume
384
Issue
6700
Pages
eadk0850-eadk0850
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.adk0850
PMC
PMC11301400
OpenAlex
W4399380870
Cited by
83
References
16
Citations by year
2026: 25 · 2025: 46 · 2024: 12
FWCI
11.30
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • U.S. Department of Defense (W81XWH2110692)
  • American Cancer Society
  • American Association for the Advancement of Science
  • Pancreatic Cancer Action Network (22-WG-DERB)
  • Lustgarten Foundation
  • Revolution Medicines
  • National Institutes of Health (5r01ca042978-30)
  • University of Texas MD Anderson Cancer Center
  • University of California, San Diego
  • National Cancer Institute (R01CA42978, P01CA203657, K99CA276700, CA016086, R35CA232113, T32CA009156, F31CA275260, P50CA196510, F32CA239328, R01-CA042978, F32CA232529, U01CA199235, F30CA243253, R35CA197588, P50CA257911, P01CA117969, R37CA251877, R00CA276700, P30CA016086, T32CA071341)
  • National Institute of General Medical Sciences (CA016086, R01GM138520, T32GM119999)
  • U.S. National Library of Medicine
  • Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill (CA016086, P30-CA016086)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
ERK1, ERK2, KRAS mutation, pancreatic cancer, phosphoproteome, MAPK signaling, Rho GTPases, oncogenic Ras, cancer cell growth
MeSH terms
Animals, Humans, Mutation, Pancreatic Neoplasms, Phosphoproteins, Phosphorylation, Proto-Oncogene Proteins p21(ras), Cyclin-Dependent Kinases, Mitogen-Activated Protein Kinase 1, Proteome, MAP Kinase Signaling System, Cell Line, Tumor, Mitogen-Activated Protein Kinase 3, Mice, HEK293 Cells

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