Abstract 3999: Advanced lung adenocarcinoma cell bank (ALACB) : A comprehensive preclinical platform

Abstract

Abstract Purpose: Patients with advanced lung adenocarcinoma often lack large clinical specimens required for molecular testing which limits next therapeutic options. Patient-derived cells (PDC) from malignant effusions can predict patient drug responses and provide a valuable tool for studying drug resistance mechanisms. In this study, we created an Advanced Lung Adenocarcinoma Cell Bank (ALACB) consisting of 28 unique PDCs established from patients who progressed on various tyrosine kinase inhibitor TKIs including 3rd generation EGFR TKI osimertinib. Experimental design: Patient malignant effusion samples were tested for malignancy, processed, observed by light microscopy, and cultured with appropriate media and supplements. The criteria for established PDCs include the following: sharing the same driver mutation as the patient; free of stromal fibroblasts confirmed by FACS staining; recapitulating patient’s drug response; and can be cryopreserved and re-grown. Established PDCs were further authenticated by STR profiling and microplasma testing to maintain cell quality. We were able to perform various in vitro assays and next generation sequencing for detailed analysis of individual PDC. Results: We were able to successfully establish 28 PDCs incorporating unique patient characteristics. Among the total 146 samples, we observed a success rate of 30% only accounting 95 malignancy positive samples. Established PDCs consists of 20 EGFR mutation positive cell lines, 3 with ALK rearrangements, 6 with ROS1 rearrangements, 1 with BRAF K601E mutation and 1 with KRAS G12D mutation. Seven PDCs were established from patients who progressed on osimertinib, two from olmutinib (HM61713), and others from 1st and 2nd generation EGFR TKI such as gefitininb and erlotinib. We were able to newly generate 3 PDCs harboring a T790M mutation with an activating EGFR mutation. Moreover, we are one of the few labs to successfully establish an EGFR del19/T790M/C797S triple mutant PDC showing resistance to osimertinib treatment in vitro. Other established PDCs harbored rare EGFR mutations including exon 20 insertion, L861Q and G719X/S768I. PDC with EGFR G719X/S768I compound mutation showed high sensitivity to afatinib but was resistant to gefitininb and osimertinib treatment. Three ALK-positive PDCs were derived from crizotinib-resistant, alectinib-resistant and ceritinib-resistant tumors. Furthermore, of 6 ROS1 fusion positive PDCs, 3 were derived from TKI-naïve tumors, and 3 from crizotinib-resistant tumors. Conclusions: Successfully established PDCs reflecting patient genomic profiles and drug response is a valuable resource for biological assays, generating in vitro drug-resistant models, and evaluating novel drugs and therapeutic targets. Further advances in drug development combined with a library of cell bank will facilitate lung cancer translational research. Citation Format: Hyeong-Seok Joo, Dong Hwi Kim, Seok-Young Kim, Ji-Yeon Lee, Mi-Ran Yun, Han-Na Kang, Byoung Chul Cho, Hye Ryun Kim. Advanced lung adenocarcinoma cell bank (ALACB) : A comprehensive preclinical platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3999.