CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin
Simone Di Franco1, Barbara Parrino2, Miriam Gaggianesi1
1Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Università degli Studi di Palermo, Palermo, Italy.
Abstract:
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.
Insights
A new drug, nortopsentin 234 (NORA234), initially reduces colorectal cancer (CRC) stem cell growth but triggers resistance. Combining NORA234 with CHK1 inhibitors offers a promising new CRC treatment strategy.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Advanced colorectal cancer (CRC) has limited treatment options.
- CRC stem cells (CR-CSphCs) can develop resistance to therapies.
- CD44v6 expression and Wnt pathway activation are linked to treatment resistance.
Purpose of the Study:
- To investigate the effects of nortopsentin 234 (NORA234) on colorectal cancer stem cells.
- To identify mechanisms of resistance to NORA234.
- To explore combination therapies for enhanced CRC treatment.
Main Methods:
- Treatment of CR-CSphCs and organoids with NORA234.
- Analysis of CD44v6 expression and Wnt pathway activity.
- Assessment of cell cycle, DNA damage response (CHK1 activation), and cell death.
- Evaluation of synergistic effects of NORA234 combined with CHK1 inhibitor (rabusertib).
Main Results:
- NORA234 initially reduced CR-CSphC proliferation and clonogenicity but led to resistant subpopulations expressing CD44v6 and activated Wnt pathway.
- NORA234 induced genotoxic stress and G2-M cell cycle arrest, activating CHK1 for DNA repair in CR-CSphCs.
- Combination therapy with NORA234 and rabusertib demonstrated synthetic lethality, causing death in both CD44v6-positive and -negative CRC stem cell fractions.
Conclusions:
- NORA234 exhibits initial efficacy against CRC stem cells but selects for resistant cells.
- CHK1 activation is a key DNA damage response mechanism in NORA234-treated CR-CSphCs.
- Combined targeting of NORA234 and CHK1 presents a potential synthetic lethal strategy for treating diverse colorectal cancer patient populations.
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