Br J Cancer:CX-5461, in combination with TOP1 inhibition, enhances the response to comotopous recombinant DNA damage in high-level slurry ovarian cancer and inhibits tumor growth

High-level slurry ovarian cancer (HGSC) is the most common histological subtype of anthopedic ovarian cancer, with the worst prognostication.
HGSC features include almost universal TP53 gene mutations, and 50% of HGSC patients have defects in HR-related dna repair genes, most commonly found in the BRCA1 and BRCA2 genes.
HR deficiencies are a key determinant of HGSC's sensitivity to standard DNA-destroying chemotherapy methods (carpentin/cisplatin and yew alcohol) and PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib).
and HR recovery is a common mechanism for obtainive resistance, which can lead to patient death, indicating the need for further development of new treatments for HR-effective diseases.
previous studies of gene networks identified by genome-wide RNAi screening have shown that the RNA gene (rDNA) transcription inhibitor CX-5461 (used in the treatment of cancer in early clinical trials) has potential applications in the treatment of HR deficiency HGSC.
the study, the researchers screened the entire protein-coded genome to identify potential targets in HR-valid HGSC that worked in synergy with CX-5461.
CX-5461 Joint Topology Inhibits HR Effective HGSC Cloning Survival and Tumor Growth Researchers found that cells that knocked out TOP1 (DNA Topology Isomerase 1) had significant inhibitory cell proliferation.
the clinically used TOP1 inhibitor topology topotecan in combination with CX-5461, cell stagnation at G2/M cell cycle checkpoints can be enhanced in a variety of HR-active HGSC cell lineages.
this combination enhances the DNA damage response and overall replication pressure without increasing the fracture of the DNA strand, thereby significantly reducing the survival rate of cloning in the body and inhibiting tumor growth.
, the findings reveal the potential for TOP1 inhibition combined with the use of CX-5461 as a non-heritogeneic treatment for HR-effective HGSC.