iScience
Volume 24, Issue 6, 25 June 2021, 102664
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Article
CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin

https://doi.org/10.1016/j.isci.2021.102664Get rights and content
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Highlights

  • CR-CSCs acquire a long-term resistance to the NORA234 treatment

  • Replicative and genotoxic stress induces the activation of CHK1

  • Adaptive response to NORA234 is associated with high expression levels of CHK1

  • NORA234 together with targeting of CHK1 leads to depletion of CR-CSC compartment

Summary

Limited therapeutic options are available for advanced colorectal cancer (CRC). Herein, we report that exposure to a neo-synthetic bis(indolyl)thiazole alkaloid analog, nortopsentin 234 (NORA234), leads to an initial reduction of proliferative and clonogenic potential of CRC sphere cells (CR-CSphCs), followed by an adaptive response selecting the CR-CSphC-resistant compartment. Cells spared by the treatment with NORA234 express high levels of CD44v6, associated with a constitutive activation of Wnt pathway. In CR-CSphC-based organoids, NORA234 causes a genotoxic stress paralleled by G2-M cell cycle arrest and activation of CHK1, driving the DNA damage repair of CR-CSphCs, regardless of the mutational background, microsatellite stability, and consensus molecular subtype. Synergistic combination of NORA234 and CHK1 (rabusertib) targeting is synthetic lethal inducing death of both CD44v6-negative and CD44v6-positive CRC stem cell fractions, aside from Wnt pathway activity. These data could provide a rational basis to develop an effective strategy for the treatment of patients with CRC.

Subject areas:

Cancer
Cell Biology
Drugs
Molecular Physiology

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These authors contributed equally

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