Tala Tayoun,¹ Vincent Faugeroux,² Marianne Oulhen,² Olivier Déas,³ Judith Michels,⁴ Laura Brulle-Soumare,⁵ Stefano Cairo,³ Jean-Yves Scoazec,⁷ Virginie Marty,⁷ Agathe Aberlenc,² David Planchard,⁴ Jordi Remon,⁸ Santiago Ponce,⁹ Benjamin Besse,⁴ Patricia L. Kannouche,¹⁰ Jean-Gabriel Judde,³ Patrycja Pawlikowska,¹¹ and Françoise Farace²

Published May 5, 2022 JCI Insight

DNA damage and genomic instability contribute to non-small cell lung cancer (NSCLC) etiology and progression. However, their therapeutic exploitation is disappointing. CTC-derived eXplants (CDX) offer systems for mechanistic investigation of CTC metastatic potency and may provide rationale for biology-driven therapeutics. Four CDX models and three CDX-derived cell lines were established from NSCLC CTCs and recapitulated patient tumor histology and responseto platinum-based chemotherapy. CDX (GR-CDXL1, GR-CDXL2, GR-CDXL3, GR-CDXL4) demonstrated considerable mutational landscape similarity with patient tumor biopsy and/or single CTCs.

Truncal alterations in key DNA damage response (DDR) and genome integrity-related genes were prevalent across models and assessed as therapeutic targets in vitro, in ovo and in vivo. GR-CDXL1 presented homologous recombination deficiency linked to bi-allelic BRCA2 mutation and FANCA deletion, unrepaired DNA lesions post-mitosis and olaparib sensitivity, despite resistance to chemotherapy. SLFN11 overexpression in GR-CDXL4 led to olaparib sensitivity and was in coherence with neuroendocrine marker expression in patient tumor biopsy, suggesting a predictive value of SLFN11 in NSCLC histological transformation into SCLC. Centrosome clustering promoted targetable chromosomal instability in GR-CDXL3 cells.

These CDX unravel DDR and genome integrity-related defects as a central mechanism underpinning metastatic potency of CTCs and provide rationale for their therapeutic targeting in metastatic NSCLC.