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

Ankita Shrivastava1, Eric Nels Pederson2, Trang Uyen Nguyen1

  • 1Department 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.

Cell Reports
|June 12, 2026
PubMed

Insights

Mutant KRAS protein controls specific mRNA translation, impacting protein synthesis machinery. This discovery reveals a novel oncogenic mechanism distinct from known pathways.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The role of mutant KRAS in regulating protein synthesis is not well understood.
  • Existing knowledge points to mTOR and EIF4E-EIF4A signaling pathways in mRNA translation control.

Purpose of the Study:

  • To define KRAS-dependent translational programs.
  • To investigate how KRAS inhibition remodels these programs.
  • To elucidate the specific mechanisms by which mutant KRAS regulates mRNA translation.

Main Methods:

  • Analysis of KRAS-dependent translational programs.
  • Investigation of mRNA features (5'UTRs, RNA sequences) influencing translation.
  • Observation of ribosome accumulation on selective mRNAs.

Main Results:

  • Mutant KRAS selectively controls the translation of a subset of mRNAs.
  • These mRNAs possess short, weakly folded 5'UTRs and low folding energy consensus RNA sequences.
  • Ribosome accumulation was observed on these specific mRNAs, indicating altered translation.
  • This KRAS-dependent mechanism is distinct from mTOR and EIF4E-EIF4A signaling.

Conclusions:

  • Mutant KRAS plays an indispensable role in regulating mRNA translation.
  • KRAS selectively uncouples the translation of mRNAs encoding protein synthetic machinery.
  • This finding redefines the understanding of oncogenic regulation of mRNA translation in cancer.
Keywords:
CP: cancerCP: molecular biologyEEF1AEIF4AKRAS inhibitorsRibosomemRNA translationmTOR signalingmutant KRASoncogenic signalingribosome profilingribosome stalling, pancreatic cancer

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