Related Experiment Video
Updated: Aug 12, 2025
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
Published on: May 23, 2025
Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9
Ling Deng1, Li Yang2, Shuhan Zhu1
1Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Abstract:
There is currently a lack of efficacious treatments for patients with chemo-resistant small-cell lung cancer (SCLC), leading to poor prognoses. We examined a chemo-resistant SCLC cell line using genome-wide CRISPR/Cas9 screening and identified serine/threonine kinase cell division cycle 7 (CDC7) as a potential synergistic target. Silencing CDC7 in chemo-resistant SCLC cells decreased the IC50 and improved the efficacy of chemotherapy. Based on the highest single agent model, the CDC7 inhibitor XL413 had a synergistic effect with both cisplatin and etoposide in chemo-resistant SCLC cells, but had no such effect in chemo-sensitive SCLC cells; the combination of XL413 and chemotherapy significantly inhibited cell growth. Western blot and flow cytometry showed that the combined treatments increased apoptosis, whereas XL413 alone had little effect on apoptosis. An analysis of cell cycle and cyclin protein levels indicated that the combination of XL413 and chemotherapy-induced G1/S phase arrest and DNA damage in chemo-resistant SCLC cells. Xenografted tumor and histoculture drug response assays using patient-derived xenografts showed that XL413 improved the efficacy of chemotherapy in vivo and with SCLC tissues. These results suggest that XL413 exerts a synergistic effect with chemotherapy on chemo-resistant SCLC.
Insights
Chemo-resistant small-cell lung cancer (SCLC) has limited treatment options. Targeting serine/threonine kinase cell division cycle 7 (CDC7) with XL413 synergizes with chemotherapy, enhancing efficacy in chemo-resistant SCLC models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemo-resistant small-cell lung cancer (SCLC) presents a significant clinical challenge with poor patient prognoses.
- Current treatment strategies for chemo-resistant SCLC are limited, necessitating the exploration of novel therapeutic targets.
Purpose of the Study:
- To identify novel synergistic targets for chemo-resistant SCLC using genome-wide CRISPR/Cas9 screening.
- To evaluate the therapeutic potential of targeting serine/threonine kinase cell division cycle 7 (CDC7) in combination with chemotherapy for chemo-resistant SCLC.
Main Methods:
- Genome-wide CRISPR/Cas9 screening was employed to identify potential drug targets in a chemo-resistant SCLC cell line.
- The efficacy of the CDC7 inhibitor XL413, alone and in combination with cisplatin and etoposide, was assessed in chemo-resistant and chemo-sensitive SCLC cells.
- Western blot, flow cytometry, cell cycle analysis, and xenografted tumor assays were used to investigate the mechanisms of action and in vivo efficacy.
Main Results:
- Genome-wide screening identified CDC7 as a potential synergistic target in chemo-resistant SCLC.
- XL413 demonstrated a synergistic effect with cisplatin and etoposide specifically in chemo-resistant SCLC cells, significantly inhibiting cell growth.
- Combined treatment with XL413 and chemotherapy induced apoptosis, G1/S phase arrest, and DNA damage, with validated efficacy in patient-derived xenografts.
Conclusions:
- CDC7 inhibition, particularly with XL413, synergizes with standard chemotherapy agents to overcome chemoresistance in SCLC.
- XL413 represents a promising therapeutic strategy to improve treatment outcomes for patients with chemo-resistant SCLC.
