Targeting genome integrity dysfunctions impedes metastatic potency in non-small cell lung cancer circulating tumor...

Area of Science:

• Oncology
• Genetics
• Cancer Biology

Background:

• DNA damage and genomic instability are key drivers in non-small cell lung cancer (NSCLC) development and progression.
• Therapeutic strategies targeting these defects in NSCLC have yielded disappointing results.
• Circulating tumor cell-derived explants (CDX) provide a platform for studying cancer cell biology and developing targeted therapies.

Purpose of the Study:

• To establish and characterize CDX models from NSCLC CTCs.
• To investigate the role of DNA damage response (DDR) and genome integrity defects in CTCs.
• To explore the therapeutic potential of targeting these defects in metastatic NSCLC.

Main Methods:

• Generation of four CDX models and three CDX-derived cell lines from NSCLC CTCs.
• Genomic profiling of CDX models to assess mutational landscape similarity with patient tumors.
• In vitro, in ovo, and in vivo assessment of therapeutic targets, including DNA damage response pathways and related genes.

Main Results:

• CDX models recapitulated patient tumor histology and chemotherapy response.
• Significant mutational landscape similarity was observed between CDX models and patient tumor biopsies/single CTCs.
• Specific DDR defects, such as homologous recombination deficiency (BRCA2, FANCA) and SLFN11 overexpression, were identified, correlating with drug sensitivity (olaparib).
• Centrosome clustering was linked to chromosomal instability in one CDX model, indicating a targetable defect.

Conclusions:

• CDX models are effective systems for studying CTC metastatic potential and identifying therapeutic targets.
• DDR and genome integrity defects are central to the metastatic capability of NSCLC CTCs.
• Targeting these specific genomic vulnerabilities in CTCs presents a promising strategy for treating metastatic NSCLC.