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Updated: May 27, 2026
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy
M Bartucci1, S Svensson, P Romania
1Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
Abstract:
Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.
Insights
Chemoresistant cancer stem cells (CSCs) in non-small-cell lung cancer (NSCLC) survive chemotherapy via cell cycle arrest. Inhibiting Chk1 kinase with chemotherapy overcomes this resistance, improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Chemoresistance in cancer stem cells (CSCs) is a major cause of poor clinical outcomes in non-small-cell lung cancer (NSCLC).
- Understanding the molecular mechanisms of chemoresistance in NSCLC CSCs is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the DNA damage response in NSCLC CSCs.
- To identify molecular targets for overcoming chemoresistance in NSCLC.
Main Methods:
- Investigated DNA damage response in NSCLC CSCs and differentiated cells following chemotherapy exposure.
- Assessed the role of checkpoint kinase 1 (Chk1) activation in chemoresistance.
- Evaluated the efficacy of Chk1 inhibitors combined with chemotherapy in vitro and in vivo models.
Main Results:
- NSCLC CSCs exhibit cell cycle arrest and DNA repair upon chemotherapy, mediated by early and significant Chk1 activation, irrespective of p53 status.
- Differentiated NSCLC cells show weak Chk1 activation and increased sensitivity to chemotherapy.
- Combining Chk1 inhibitors (e.g., AZD7762) with chemotherapy significantly reduced NSCLC CSC survival, induced mitotic catastrophe, abrogated tumor growth in vivo, and reduced CSC populations.
Conclusions:
- Chk1 activation is a key mechanism of chemoresistance in NSCLC CSCs.
- Co-administration of Chk1 inhibitors and chemotherapy demonstrates significant therapeutic potential by targeting NSCLC CSCs.
- Clinical evaluation of Chk1 inhibitors in combination with chemotherapy is warranted for improved NSCLC treatment.
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