The Cuto Panel Of Patient-Derived Nsclc Cell Lines Reveals Unique Molecular Characteristics And Responses To Targeted Therapies

Cell lines generated from human tumors have been an invaluable tool in dissecting the underlying molecular mechanisms of cancer biology and for cancer drug development. The large library of original human lung cancer cell lines established by Minna and Gazdar, though instrumental in investigating various aspect of lung cancer biology, lacks examples of some of the diverse mutations responsible for this cancer. The CUTO (Colorado University Thoracic Oncology) cell line series, initiated in 2011, had the goal of curating a new panel of cells derived from NSCLC patients with distinct oncogenic drivers. By generating multiple, unique cell lines representing each oncogene driver subset, we believe that these lines would allow study of interpatient variability that underlie differential patient responses and duration of response to targeted therapies. The current CUTO panel consist of 33 cell lines with either 1) gene rearrangements in ALK, RET, ROS1 or NTRK1; 2) activating mutations in the ERBB gene family including exon 20 insertions in EGFR and ERBB2 (HER2) as well as rare mutations in EGFR; and 3) inactivation of the NF1 gene either as a concurrent mutation with other oncogenic alterations or as the sole driver mutation. For cells harboring gene rearrangements we have amassed four EML4-ALK lines, two KIF5B-RET cell lines, five ROS1 fusion lines (3 CD74-ROS1, 1 SDC4-ROS1, and 1 TPM3-ROS1), and one MPRIP-NTRK1 cell line. Our ERBB mutant lines include one cell line with HER2 exon 20 insertion, three lines with different exon 20 insertions in EGFR, and two EGFR mutant cell lines with compound mutations. We present our characterization of these cell lines in terms of their proliferation profiles and molecular signaling pathways in the presence of targeted inhibition. The derivation and characterization of these cell lines have facilitated the study of cell signaling in oncogene-driven cancer, have helped identify new resistance mechanisms, and have facilitated drug development for rare oncogenes such as NTRK1 gene fusions and EGFR exon 20 insertions. We expect that this growing library of cell lines will continue to further our understanding of oncogenic-driven tumor biology and provide mechanistic insight towards the development of novel therapeutics and drug combinations. Citation Format: Anh Tuan Le, Adriana Estrada-Bernal, Laura Schubert, Andrea Doak, Nan Chen, Kurtis Davies, Aria Vaishnavi, Mary Jackson, Vignesh Narayana, Kimi Kondo, John Mitchell, Michael Weyant, Tom Purcell, Paul Bunn, Ross Camidge, Janet Freeman-Daly, Robert Doebele. The CUTO panel of patient-derived NSCLC cell lines reveals unique molecular characteristics and responses to targeted therapies [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr A29.