Abstract 1951: Circulating tumor cell-derived explant models reveal DNA damage response-based therapeutic opportunities in non-small cell lung cancer

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Abstract Background: 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 biology-driven therapeutic testings. We perform in-depth molecular and functional characterization of CDX models and demonstrate that targeting defects in the DNA damage response (DDR) and genome integrity regulators impedes CTC-driven metastasis in NSCLC. Methods: CTCs were enriched from 30 mL blood samples of 56 advanced NSCLC patients and implanted subcutaneously into Nod/Scid-IL2Rγ-/- (NSG) mice. Tumors were palpable within a median of 108 days. Among the four CDX models established, three CDX-derived cell lines (GR-CDXL1, GR-CDXL3, GR-CDXL4) were obtained. CDX and cell lines were characterized by immunofluorescence (IF), immunohistochemistry and whole-exome sequencing (WES). Chromosomal instability (CIN) and DDR activity were evaluated by IF and western blot. Gene expression was quantified by qRT-PCR. Tumorigenic potential of CDX-derived cell lines was assessed in the chick embryo chorioallantoic membrane and NSG mice engrafted intravenously. IC50 was assessed using CellTiter-Glo®. Results: Four CDX models and three CDX-derived cell lines were established from NSCLC CTCs and recapitulated patient tumor histology (available for three patients) and response to platinum-based chemotherapy. WES analysis showed considerable mutational landscape similarity between the CDX (GR-CDXL1, GR-CDXL2, GR-CDXL3, GR-CDXL4), corresponding patient tumor biopsy and/or single CTCs. Truncal alterations in key 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, FANCA deletion and unrepaired DNA lesions post-mitosis. GR-CDXL1 cells were sensitive to PARP inhibitor (PARPi) olaparib, despite chemoresistance, which challenges the current clinical hypothesis claiming that chemosensitive NSCLC patients should respond to PARPi. Targeting CIN through centrosome clustering inhibition in GR-CDXL3 impeded tumor growth in ovo and in vivo. In GR-CDXL4, olaparib sensitivity was dictated by SLFN11 overexpression, which also correlated with increased neuroendocrine marker expression at patient disease progression, suggesting a predictive value of SLFN11 in histological transformation of NSCLC into SCLC. Conclusion: This study unravels distinct DDR profiles as a central mechanism underpinning CTC metastatic potency. Our CDX models provide a robust platform for ex vivo drug testing of DDR-targeted strategies to expand patient categories that may benefit from precision medicine in metastatic NSCLC. Citation Format: Tala Tayoun, Vincent Faugeroux, Marianne Oulhen, Olivier Deas, Judith Michels, Laur Brulle-Soumare, Stefano Cairo, Jean-Yves Scoazec, Virginie Marty, Agathe Aberlenc, David Planchard, Jordi Remon, Santiago Ponce, Benjamin Besse, Patricia Kannouche, Jean-Gabriel Judde, Patrycja Pawlikowska, Françoise Farace. Circulating tumor cell-derived explant models reveal DNA damage response-based therapeutic opportunities in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1951.

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