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Enhancing transcription-replication conflict targets ecDNA-positive cancers

Jun Tang1,2, Natasha E Weiser1,3, Guiping Wang3,4

  • 1Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Nature
|November 7, 2024
PubMed

Insights

Extrachromosomal DNA (ecDNA) drives cancer treatment resistance. Enhancing transcription-replication conflicts, particularly by inhibiting CHK1, selectively eliminates ecDNA-containing tumors, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Extrachromosomal DNA (ecDNA) is a key driver of cancer treatment resistance and poor patient outcomes due to oncogene amplification and rapid genome evolution.
  • Currently, no treatments specifically target ecDNA, representing a significant unmet need in cancer therapy.
  • ecDNA facilitates massive oncogene transcription and rapid genome evolution, contributing to poor patient survival.

Purpose of the Study:

  • To investigate the potential of enhancing transcription-replication conflicts as a strategy for targeted elimination of ecDNA-containing cancers.
  • To identify specific molecular mechanisms underlying ecDNA's role in cancer progression and treatment resistance.
  • To develop and evaluate novel therapeutic approaches targeting ecDNA vulnerabilities.

Main Methods:

  • Analysis of ecDNA transcription and associated single-stranded DNA to quantify transcription-replication conflicts.
  • Assessment of nucleotide incorporation rates and replication stress in ecDNA-containing tumors.
  • Investigating the role of pRPA2-S33 and CHK1 activation in response to ecDNA-driven stress.
  • Evaluating the efficacy of CHK1 inhibition, including a novel inhibitor BBI-2779, in preclinical cancer models.

Main Results:

  • ecDNA exhibits higher transcription-replication conflicts and replication stress compared to chromosomal DNA.
  • CHK1 activation and DNA double-strand breaks are elevated on ecDNA in a transcription-dependent manner.
  • Genetic or pharmacological inhibition of CHK1 leads to preferential death of ecDNA-containing tumor cells.
  • The novel CHK1 inhibitor BBI-2779 demonstrates potent and selective killing of ecDNA-containing tumor cells and suppresses tumor growth in a gastric cancer model.

Conclusions:

  • Enhancing transcription-replication conflict is a viable strategy for targeted ecDNA elimination in cancer.
  • CHK1 inhibition represents a promising therapeutic avenue for treating ecDNA-driven cancers.
  • BBI-2779 shows potential as a novel, orally available drug for ecDNA-targeted cancer therapy, overcoming treatment resistance.

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