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CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells

Gwenola Manic1, Michele Signore2, Antonella Sistigu3

  • 1Department of Biology, University of Rome "Tor Vergata", Rome, Italy.

Gut
|April 9, 2017
PubMed
Abstract

Insights

A new drug, LY2606368, effectively targets cancer stem cells (CSCs) in colorectal cancer (CRC) by inducing replication stress. This offers a promising therapeutic strategy for advanced CRC, including RAS-mutated tumors.

Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Drug Discovery

Background:

  • Cancer stem cells (CSCs) drive tumor formation and metastasis, necessitating targeted therapies for effective eradication.
  • Advanced colorectal cancer (CRC), especially with RAS-activating mutations, has limited therapeutic options.
  • Targeting CSCs is crucial for improving treatment outcomes in CRC.

Purpose of the Study:

  • To identify novel strategies for targeting colorectal cancer stem cells (CRCs).
  • To discover potential single-agent therapeutics for clinical investigation.
  • To explore biomarkers predicting efficacy of novel CSC-targeting agents.

Main Methods:

  • Screening of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs).
  • Integration of genomic, reverse-phase protein microarray (RPPA), and cytogenetic analyses to identify predictive biomarkers.
  • Validation of biomarkers using immunostainings and experimental induction of DNA replication stress (RS).

Main Results:

  • LY2606368 identified as a potent anti-CSC agent, effective in vitro and in vivo in approximately 36% of patient tumors.
  • LY2606368 inhibits checkpoint kinase (CHK)1, inducing lethal DNA replication stress in most CRC-SCs, including RAS-mutated types.
  • Sensitive CRC-SCs showed signs of ongoing RS response (e.g., phosphorylated RPA32, ATM), associated with TP53 mutations and hyperdiploidy, indicating CHK1 dependency.

Conclusions:

  • LY2606368 selectively eliminates replication-stressed, p53-deficient, and hyperdiploid CRC-SCs, irrespective of RAS mutational status.
  • Experimental increase of RS sensitized resistant CRC-SCs to LY2606368, supporting its mechanism of action.
  • Results provide a strong rationale for biomarker-driven clinical trials of LY2606368 in CRC patients.
Keywords:
CELL CYCLE CONTROLCHEMOTHERAPYCOLORECTAL CANCERDNA DAMAGEDRUG DEVELOPMENT

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