Related Experiment Video

Updated: May 10, 2025

A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
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Differential unfolded protein response regulation in KRAS silencing sensitive and innately resistant colorectal

Flávia Martins1,2, Ana L Machado1,2, Joana Carvalho1,3

  • 1Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.

Scientific Reports
|April 24, 2025
PubMed

Insights

Colorectal cancer cells activate the unfolded protein response (UPR) to survive KRAS inhibition. This early adaptive mechanism in KRAS-dependent colorectal cancer (CRC) cells is key to resistance.

Area of Science:

  • Molecular Oncology
  • Cancer Cell Biology
  • Drug Resistance Mechanisms

Background:

  • Mutant-KRAS inhibitors show limited efficacy in colorectal cancer (CRC), often resulting in stable disease or rapid recurrence.
  • The molecular basis for CRC cell tolerance and resistance to KRAS inhibition is not well understood.
  • Identifying early cellular responses to KRAS inhibition is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate early transcriptional and proteomic responses to KRAS silencing in 3D CRC spheroid models.
  • To identify molecular pathways associated with sensitivity or resistance to KRAS blockade in colorectal cancer.
  • To elucidate the role of the unfolded protein response (UPR) in KRAS-dependent colorectal cancer adaptation.

Main Methods:

  • Utilized 3D CRC cell line spheroid models to mimic tumor microenvironment.
  • Stratified cell lines into KRAS silencing-sensitive and -resistant groups based on growth, cell cycle, and apoptosis.
  • Performed transcriptional profiling (RNA-seq) and proteomic analysis (membrane-enriched fractions) to identify differentially regulated pathways.

Main Results:

  • KRAS silencing-sensitive CRC cells showed upregulation of the unfolded protein response (UPR) and WNT/β-catenin signaling.
  • KRAS silencing-resistant CRC cells exhibited downregulation of these pathways.
  • Sensitive cells displayed reduced protein aggregation and translational capacity upon KRAS knockdown, consistent with UPR activation.

Conclusions:

  • Activation of the unfolded protein response (UPR) is an early adaptive response in KRAS-dependent colorectal cancer cells undergoing KRAS silencing.
  • UPR activation is a potential mechanism enabling CRC cells to tolerate KRAS inhibition.
  • Further research into targeting UPR in combination with KRAS inhibitors may overcome therapeutic resistance.

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