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Results of the Lung Cancer Cell Line Screen for OST Inhibitor Sensitivity

Deep sequencing of lung cancer cell lines to determine the proportion of EGFR mutations.

Characterization of the Osimertinib resistant H1975 cells.

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Asparagine (N)-linked glycosylation is a posttranslational modification essential for the function of complex transmembrane proteins. However, targeting glycosylation for cancer therapy has not been feasible due to generalized effects on all glycoproteins. Here, we perform sensitivity screening of 94 lung cancer cell lines using NGI-1, a small-molecule inhibitor of the oligosaccharyltransferase (OST) that partially disrupts N-linked glycosylation, and demonstrate a selective loss of tumor cell viability. This screen revealed NGI-1 sensitivity in just 11 of 94 (12%) cell lines, with a significant correlation between OST and EGFR inhibitors. In EGFR-mutant non-small cell lung cancer with EGFR tyrosine kinase inhibitor (TKI) resistance (PC9-GR, HCC827-GR, and H1975-OR), OST inhibition maintained its ability to induce cell-cycle arrest and a proliferative block. Addition of NGI-1 to EGFR TKI treatment was synthetic lethal in cells resistant to gefitinib, erlotinib, or osimertinib. OST inhibition invariably disrupted EGFR N-linked glycosylation and reduced activation of receptors either with or without the T790M TKI resistance mutation. OST inhibition also dissociated EGFR signaling from other coexpressed receptors like MET via altered receptor compartmentalization. Translation of this approach to preclinical models was accomplished through synthesis and delivery of NGI-1 nanoparticles, confirmation of in vivo activity through molecular imaging, and demonstration of significant tumor growth delay in TKI-resistant HCC827 and H1975 xenografts. This therapeutic strategy breaks from kinase-targeted approaches and validates N-linked glycosylation as an effective target in tumors driven by glycoprotein signaling.Significance: EGFR-mutant NSCLC is incurable despite the marked sensitivity of these tumors to EGFR TKIs. These findings identify N-linked glycosylation, a posttranslational modification common to EGFR and other oncogenic signaling proteins, as an effective therapeutic target that enhances tumor responses for EGFR-mutant NSCLC. Cancer Res; 78(17); 5094–106. ©2018 AACR.

Precompetitive collaboration is a term used when competitors share early stages of research and development that are beneficial to all stakeholders. This Public-Private Partnership Consortium supports research to advance technologies and use these technologies for early cancer detection, to distinguish benign disease from cancer, and to distinguish aggressive from nonaggressive cancer. Combining the complementary expertise of both academics and industry may increase the likelihood of developing a viable diagnostic assay. In the era of personalized medicine, it is desirable to have noninvasive or minimally invasive methods to determine and follow longitudinally the molecular composition and characterization of a patient’s tumor, which will help gain a broader understanding of the disease. Liquid biopsy (CTC, ctDNA, extracellular vesicles, etc.) can be used to molecularly characterize the tumor and monitor genetic changes over time using repeat sampling of biofluids. The current technologies have shown great potential in diagnosis, predicting response to therapy, and monitoring relapse; however, the biologic and analytical challenges have rendered their usefulness for early detection/screening more difficult to establish. To address these challenges, the NCI developed this cooperative agreement program to support the work of six teams. Each team consists of a group of experts that include oncologists, bioinformaticians, researchers, and at least one industry partner. The current teams are developing a variety of unique assays/technologies that range from capture enhancements, microscope integration, nanoplasmonics, to specialized machine learning algorithms and bioinformatic analyses. Ovarian, breast, lung, and brain cancers are the model systems being studied, and there are at least two teams focused on each cancer type. The Consortium conducts work with the assistance of two working subgroups, Study Design and Biorepository, in conjunction with NCI staff. To monitor progress, there are yearly face-to-face Steering Committee meetings and monthly conference calls/Webex meetings. Progress in the first year of funding has been noteworthy. One of the teams has already achieved Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathologists Certification, while another team has an insurance reimbursable extracellular vesicles test for risk assessment for prostate cancer. Citation Format: Lynn Sorbara, David Wong, Carter Bob, Richard Cote, Hakho Lee, Nickolas Papadopoulos, Abhijit Patel, Sudhir Srivastava. Precompetitive collaboration on liquid biopsy for early cancer assessment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B65.