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Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance.

ABSTRACT: Acquired resistance to cetuximab, a chimeric epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, is a widespread problem in the treatment of solid tumors. The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. The purpose of this study was to generate cetuximab-resistant tumors in vivo to characterize mechanisms of acquired resistance.We generated cetuximab-resistant clones from a cetuximab-sensitive bladder cancer cell line in vivo by exposing cetuximab-sensitive xenografts to increasing concentrations of cetuximab, followed by validation of the resistant phenotype in vivo and in vitro using invasion assays. A candidate-based approach was used to examine the role of HER2 on mediating cetuximab resistance both in vitro and in vivo.We generated a novel model of cetuximab resistance, and, for the first time in the context of EGFR-inhibitor resistance, we identified increased phosphorylation of a C-terminal fragment of HER2 (611-CTF) in cetuximab-resistant cells. Afatinib (BIBW-2992), an irreversible kinase inhibitor targeting EGFR and HER2, successfully inhibited growth of the cetuximab-resistant cells in vitro. When afatinib was combined with cetuximab in vivo, we observed an additive growth inhibitory effect in cetuximab-resistant xenografts.These data suggest that the use of dual EGFR-HER2 kinase inhibitors can enhance responses to cetuximab, perhaps in part due to downregulation of 611-CTF. This study conducted in a novel in vivo model provides a mechanistic rationale for ongoing phase I clinical trials using this combination treatment modality.

SUBMITTER: Quesnelle KM

PROVIDER: S-EPMC3426303 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance.

Quesnelle Kelly M KM Grandis Jennifer R JR

Clinical cancer research : an official journal of the American Association for Cancer Research 20110726 18

<h4>Purpose</h4>Acquired resistance to cetuximab, a chimeric epidermal growth factor receptor (EGFR)-targeting monoclonal antibody, is a widespread problem in the treatment of solid tumors. The paucity of preclinical models has limited investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. The purpose of this study was to generate cetuximab-resistant tumors in vivo to characterize mechanisms of acquired resistance.< ...[more]

PMID: 21791633

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Project description:Cetuximab, the FDA-approved anti-EGFR antibody for head and neck squamous cell carcinoma (HNSCC), has displayed limited efficacy due to the emergence of intrinsic and acquired resistance. We and others have demonstrated that cetuximab resistance in HNSCC is driven by alternative receptor tyrosine kinases (RTK), including HER3, MET, and AXL. In an effort to overcome cetuximab resistance and circumvent toxicities associated with the administration of multiple RTK inhibitors, we sought to identify a common molecular target that regulates expression of multiple RTK. Bromodomain-containing protein-4 (BRD4) has been shown to regulate the transcription of various RTK in the context of resistance to PI3K and HER2 inhibition in breast cancer models. We hypothesized that, in HNSCC, targeting BRD4 could overcome cetuximab resistance by depleting alternative RTK expression. We generated independent models of cetuximab resistance in HNSCC cell lines and interrogated their RTK and BRD4 expression profiles. Cetuximab-resistant clones displayed increased expression and activation of several RTK, such as MET and AXL, as well as an increased percentage of BRD4-expressing cells. Both genetic and pharmacologic inhibition of BRD4 abrogated cell viability in models of acquired and intrinsic cetuximab resistance and was associated with a robust decrease in alternative RTK expression by cetuximab. Combined treatment with cetuximab and bromodomain inhibitor JQ1 significantly delayed acquired resistance and RTK upregulation in patient-derived xenograft models of HNSCC. These findings indicate that the combination of cetuximab and bromodomain inhibition may be a promising therapeutic strategy for patients with HNSCC.Significance: Inhibition of bromodomain protein BRD4 represents a potential therapeutic strategy to circumvent the toxicities and financial burden of targeting the multiple receptor tyrosine kinases that drive cetuximab resistance in HNSCC and NSCLC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4331/F1.large.jpg Cancer Res; 78(15); 4331-43. ©2018 AACR.

Project description: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.

Dataset Information

Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance.

Publications

Dual kinase inhibition of EGFR and HER2 overcomes resistance to cetuximab in a novel in vivo model of acquired cetuximab resistance.

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