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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Colorectal cancer with V600E BRAF mutations (BRAFMT) has a poor prognosis.
  • Current anti-BRAF/EGFR therapies show limited efficacy in BRAFMT colorectal cancer.
  • Understanding BRAFMT colorectal cancer biology is crucial for developing new treatments.

Purpose of the Study:

  • To investigate the biological pathways in BRAFMT colorectal cancer.
  • To evaluate the sensitivity of BRAFMT colorectal cancer cells to the unfolded protein response (UPR) activator BOLD-100.
  • To identify novel combination strategies for BOLD-100 in BRAFMT colorectal cancer.

Main Methods:

  • Differential gene expression analysis of BRAF wild-type (BRAFWT) and BRAFMT colorectal cancer cells.
  • Sensitivity testing of molecularly subtyped colorectal cancer cells to BOLD-100.
  • RNA sequencing and high-throughput drug screening to identify combination strategies.
  • Systems biology approach to identify resistance mechanisms.

Main Results:

  • UPR and DNA repair pathways were significantly enriched in BRAFMT colorectal cancer.
  • Oncogenic BRAF is critical for the response to BOLD-100.
  • V600EBRAFMT-dependent activation of ataxia telangiectasia and Rad3-related (ATR) kinase mediates resistance to BOLD-100.
  • BOLD-100 treatment induced reactive oxygen species (ROS) and activated the ATR/CHK1 pathway, leading to apoptosis.
  • The ROS/ATR/CHK1 pathway activation was mediated by the AhR transcription factor and CYP1A1.
  • ATR inhibitors synergistically enhanced BOLD-100-induced apoptosis and growth inhibition in BRAFMT models.

Conclusions:

  • BOLD-100 induces BRAFMT-dependent replication stress.
  • Targeting the replication stress response pathway, specifically with ATR inhibitors, in combination with BOLD-100, presents a novel therapeutic strategy.
  • This combination therapy may offer a new treatment option for aggressive BRAFMT colorectal cancer.