Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening

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.

Engineering CRISPR/Cas9 therapeutics for cancer precision medicine

“…Cell division cycle 7 (CDC7) was identified by Deng. et al using CRISPR/Cas9 screening ( Deng et al, 2023 ). In chemo-resistant small cell lung cancer, CDC7 possibly acts as synergistic target ( Deng et al, 2023 ).…”

“…et al using CRISPR/Cas9 screening ( Deng et al, 2023 ). In chemo-resistant small cell lung cancer, CDC7 possibly acts as synergistic target ( Deng et al, 2023 ). Studies revealed that suppressing CDC7 lowered the IC50 and increased chemotherapy effectiveness in chemo-resistant SCLC cells ( Deng et al, 2023 ).…”

“…In chemo-resistant small cell lung cancer, CDC7 possibly acts as synergistic target ( Deng et al, 2023 ). Studies revealed that suppressing CDC7 lowered the IC50 and increased chemotherapy effectiveness in chemo-resistant SCLC cells ( Deng et al, 2023 ). Another CRISPR/Cas9 screen has identified a Zinc transporter (ZIP9) and using CRISPR-mediated ZIP9 deletion showed that knockout of ZIP9 causes dysregulation of Zinc homeostasis, which is associated with N-terminal linked glycosylation resulting in cancer-like glycosylation on the surface of the cell surface ( Wang et al, 2020 ).…”

CRISPR-Cas and CRISPR-based screening system for precise gene editing and targeted cancer therapy

“…The CRISPR/Cas9 screening in chemo-resistant small-cell lung cancer (SCLC) identified serine/threonine kinase cell division cycle 7 (CDC7) as a potential synergistic target. Combination of CDC7 inhibitor XL413 and chemotherapy led to apoptosis of chemo-sensitive SCLC in xenograft tumor [ 132 ]. Acute Myeloid Leukemia (AML) cell lines such as MOLM-13, MV4-11, HL-60, OCI-AML2, OCI-AML3 were examined for therapeutic targets via genome-wide CRISPR screening, indicating KAT2A inhibition as a therapeutic strategy in AML [ 133 ].…”

Applications of CRISPR screening to lung cancer treatment

“…A genome-scale CRISPR/Cas9 deletion screen in DDP- and VP16-treated and untreated resistant SCLC cells results in the identification of the serine/threonine kinase cell division cycle 7 (CDC7) as a promising target for chemotherapeutic synergy. The combined use of CDC7 inhibitors and other drugs helps to overcome chemoresistance in the treatment of SCLC and improves patient prognosis ( Deng et al, 2023 ). A human-genome-wide library was employed to screen the genes necessary for CHK1i sensitivity in lung cancer cells, and several MMB-FOXM1 complex components were discovered ( Branigan et al, 2021 ).…”