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Rewriting the cancer proteome: targeting selective translation as a therapeutic frontier

Davide Ruggero1,2,3

  • 1Helen Diller Family Comprehensive Cancer Center.

The Journal of Clinical Investigation
|June 15, 2026
PubMed

Insights

Cancer cells manipulate protein production through selective translation, not just RNA levels. Inhibiting eIF4E in prostate cancer restored hormone sensitivity by altering protein synthesis, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Translational Medicine

Background:

  • Cancer proteogenomics reveals a disconnect between RNA levels and protein output, emphasizing the role of translation in cancer.
  • Malignant cells can exploit selective translation processes to maintain their identity, survival, and resistance to therapies.

Purpose of the Study:

  • To investigate the impact of inhibiting eukaryotic initiation factor 4E (eIF4E) cap binding on the prostate cancer translatome.
  • To determine if targeting selective translation can re-sensitize prostate cancer to hormone therapy.

Main Methods:

  • Pharmacologic inhibition of eIF4E cap binding in prostate cancer models.
  • Analysis of the translatome to identify changes in protein synthesis.
  • Assessment of phenotypic changes and therapeutic sensitivity.

Main Results:

  • Inhibition of eIF4E selectively rewired the prostate cancer translatome.
  • Suppression of basal keratin translation and promotion of luminal features were observed.
  • Renewed sensitivity to hormone therapy was achieved.

Conclusions:

  • Tumors utilize selective translation to maintain lineage plasticity, survival, and therapeutic resistance.
  • Targeting translational dependencies can dismantle cancer-specific proteomic programs.
  • Exploiting vulnerabilities in selective translation may convert resistant cancer states into druggable targets.

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