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Disrupting KRAS-AGO2 interaction: a dual-pronged strategy to sensitize chemo-immunotherapy in KRAS-mutated colorectal

Jingyi Xie1,2, Simeng Wang1, Juan Liu3

  • 1Department of Endocrinology and Metabolism and International Joint Research Center for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.

Apoptosis : an International Journal on Programmed Cell Death
|August 20, 2026
PubMed

Insights

A novel peptide-gold nanoparticle therapy disrupts KRAS-AGO2 interaction, restoring microRNA (miRNA) let-7c-5p to suppress KRAS-mutated colorectal cancer (CRC) growth and enhance treatment sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Nanotechnology

Background:

  • KRAS mutations are common in colorectal cancer (CRC), leading to poor prognosis and treatment resistance.
  • Mutated KRAS interacts with Argonaute 2 (AGO2), impairing microRNA (miRNA) function and promoting tumor progression.
  • Current therapies for KRAS-mutated CRC have limited efficacy.

Purpose of the Study:

  • To investigate the therapeutic potential of disrupting the KRAS-AGO2 interaction in KRAS-mutated CRC.
  • To develop and evaluate a peptide-gold nanoparticle (Au-pep) inhibitor targeting the KRAS-AGO2 complex.
  • To elucidate the underlying molecular mechanisms of Au-pep treatment.

Main Methods:

  • Development of peptide-gold nanoparticles (Au-pep) to specifically inhibit KRAS-AGO2 interaction.
  • Assessment of Au-pep's effect on the malignant phenotype of KRAS-mutated CRC cells.
  • Analysis of miRNA expression landscape changes and identification of key miRNA effectors.
  • Evaluation of Au-pep's impact on oncogenic driver expression (KRAS, c-Myc, Bcl2).
  • Investigation of Au-pep's synergistic effects with 5-fluorouracil (5-FU) and immunotherapy.

Main Results:

  • Au-pep treatment significantly attenuated the malignant phenotype of KRAS-mutated CRC cells.
  • Disruption of the KRAS-AGO2 complex partially restored miRNA expression, notably up-regulating let-7c-5p.
  • Restored let-7c-5p down-regulated oncogenic drivers (KRAS, c-Myc, Bcl2), suppressing CRC cell growth and inducing apoptosis.
  • Au-pep sensitized CRC cells to 5-FU by repressing ABCC5 and enhanced immunotherapy response via PD-L1 down-regulation.

Conclusions:

  • Disrupting the KRAS-AGO2 interaction with Au-pep offers a novel therapeutic strategy for KRAS-mutated CRC.
  • This approach restores miRNA function, suppresses tumor growth, and overcomes therapeutic resistance.
  • The findings present a promising therapeutic paradigm with significant translational potential for recalcitrant CRC patients.
Keywords:
KRAS mutationsAGO2Chemo-immunotherapy resistanceColorectal cancer (CRC)Let-7c-5p

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