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.