2. Academic Validation
  3. Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer

Mutant KRAS-driven selective mRNA translation reveals mechanisms and therapeutic vulnerabilities in cancer

  • Cell Rep. 2026 Jun 23;45(6):117520. doi: 10.1016/j.celrep.2026.117520.
Ankita Shrivastava 1,  Eric Nels Pederson 2,  Trang Uyen Nguyen 1,  Jacky Chuen 1,  Prathibha Mohan 1,  Shivangi Pande 1,  Ana Ruiz Toribio 3,  Nicolas Lecomte 4,  Jerry Melchor 4,  John C McAuliffe 5,  Paul M Grandgenett 6,  Vinagolu K Rajasekhar 7,  Kaila Nishikawa 8,  Anna Knörlein 9,  Yael David 10,  Ian M Willis 11,  Christine A Iacobuzio-Donahue 4,  Zhengqing Ouyang 2,  Kamini Singh 12
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, Stem Cell and Cancer Biology Program, Immunotherapy for Cancer and Inflammatory Disorders, Cancer Dormancy Institute, Data Science Institute, Albert Einstein College of Medicine, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY 10461, USA.
  • 2 Department of Biostatistics and Epidemiology, School of Public Health and Health Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA.
  • 3 Department of Molecular Pharmacology, Stem Cell and Cancer Biology Program, Immunotherapy for Cancer and Inflammatory Disorders, Cancer Dormancy Institute, Data Science Institute, Albert Einstein College of Medicine, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY 10461, USA; University Francisco de Vitoria, 28223 Madrid, Spain.
  • 4 David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Department of Surgery and Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA.
  • 6 Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 7 Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
  • 8 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA.
  • 9 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Tri-Institutional PhD Program in Chemical Biology, New York, NY, USA; Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
  • 11 Department of Biochemistry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461, USA.
  • 12 Department of Molecular Pharmacology, Stem Cell and Cancer Biology Program, Immunotherapy for Cancer and Inflammatory Disorders, Cancer Dormancy Institute, Data Science Institute, Albert Einstein College of Medicine, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY 10461, USA. Electronic address: [email protected].
PMID: 42284146 DOI: 10.1016/j.celrep.2026.117520
Abstract

Mutant KRAS-driven control of protein synthesis remains poorly defined. Here, we define KRAS-dependent translational programs and their acute remodeling upon KRAS inhibition. We find that mutant KRAS controls the translation of a subset of mRNAs and affects the production of proteins of the mRNA translation apparatus. Interestingly, these specific subsets of mRNAs have short, weakly folded 5'UTRs and harbor low folding energy consensus RNA sequences. We observe ribosome accumulation on selective mRNAs. Our findings clarify the indispensable role of mutant KRAS in regulating mRNA translation, setting it apart from the Other previously known mechanisms that depend on mTOR and EIF4E-EIF4A signals. Our findings uncover a mechanism by which mutant KRAS selectively uncouples the translation of mRNAs for protein synthetic machinery from the broader mRNA pool, redefining our understanding of the oncogenic regulation of mRNA translation in Cancer.

Keywords

CP: cancer; CP: molecular biology; EEF1A; EIF4A; KRAS inhibitors; Ribosome; mRNA translation; mTOR signaling; mutant KRAS; oncogenic signaling; ribosome profiling; ribosome stalling, pancreatic cancer.

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