Abstract 6208: Patient-derived organoids from oncogene-addicted lung cancers to define molecular circuits involved in drug resistance

Lung cancer represents the leading cause of cancer-related mortality worldwide, with NSCLC being the most common type. Two-thirds of NSCLC patients harbor oncogenic driver alterations, among which EGFR activating mutations and ALK rearrangements occur in 16% and 5% of cases, respectively. However, in both genetic backgrounds the benefit of molecular therapies, including next generation Tyrosine Kinase Inhibitors (TKIs), is temporally limited with therapy evasion representing a major roadblock against cancer eradication. Patient Derived Organoids (PDOs) have raised a tremendous interest in cancer research for their ability to preserve the original tumoral architecture, including its microenvironment, at both the genomic and functional level. Notably, PDOs can be stabilized from a very limited amount of starting material, such as needle biopsies from local and distal metastases, including lesions originated upon molecular therapy relapse. The possibility to perform pharmacogenomic screening and functional analyses renders PDOs an ideal tool for co-clinical studies. Thereby, we have systematically collected 87 oncogene-addicted lung cancer specimens, among which 48 were suitable for 3D cultures in terms of tumor cell number and viability. We successfully established 15 long-term PDO cultures that maintain the proliferation capability throughout passages, and obtained a subset of corresponding 2D cell lines. Histological and immunohistochemical analyses revealed that PDOs faithfully recapitulate the features of the original neoplastic lesions. Moreover, targeted molecular annotation confirmed that our PDOs retained the somatic oncogene alterations of the matching tumors. In addition, drug sensitivity tests and functional experiments have demonstrated the ability of PDOs to reproduce patient response to targeted therapies, indicating the translational relevance of our platform. Furthermore, we exploited organoids to study the molecular circuits responsible for tumor cell evasion to targeted therapy, identifying bypass track signaling as critical for the emergence of drug resistance. Finally, we tested the therapeutic efficacy of drug treatments based on the combination of early and next generations TKIs. Overall, our data highlight the translational relevance of PDO interrogation in clinical oncology, especially for patients who relapse to different lines of therapy. We provide evidence that in oncogene-addicted tumors bypass track signaling is a common non-genetic mechanism of resistance to last generation TKIs. Thus, the correct co-administration of different molecules and/or the use of earlier-generation inhibitors upon progression may improve treatment strategies, potentially impacting on patient’s benefit and clinical outcome. Citation Format: Francesca Picca, Francesca Bersani, Fabrizio Tabbo', Francesca Napoli, Paolo Bironzo, Angela Listi', Francesco Passiglia, Marco Volante, Giorgio Vittorio Scagliotti, Luisella Righi, SIlvia Novello, Riccardo Taulli. Patient-derived organoids from oncogene-addicted lung cancers to define molecular circuits involved in drug resistance [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 6208.