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Synergistic Inhibition of Kinase Pathways Overcomes Resistance of Colorectal Cancer Spheroids to Cyclic Targeted Therapies.

ABSTRACT: Cancer cells often adapt to single-agent treatments with chemotherapeutics. Activation of alternative survival pathways is a major mechanism of drug resistance. A potential approach to block this feedback signaling is using combination treatments of a pair of drugs, although toxicity has been a limiting factor. Preclinical tumor models to identify mechanisms of drug resistance and determine low but effective combination doses are critical to effectively suppress tumor growth with reduced toxicity to patients. Using our aqueous two-phase system microtechnology, we developed colorectal tumor spheroids in high-throughput and evaluated resistance of cancer cells to three mitogen-activated protein kinase inhibitors (MAPKi) in long-term cyclic treatments. Our quantitative analysis showed that the efficacy of MAPKi significantly reduced over time, leading to an increase in proliferation of HCT116 colorectal cancer cells and growth of spheroids. We established that resistance was due to feedback activation of PI3K/AKT/mTOR pathway. Using high-throughput, dose-dependent combinations of each MAPKi and a PI3K/mTOR inhibitor, we identified low-dose, synergistic combinations that blocked resistance to MAPKi and effectively suppressed the growth of colorectal tumor spheroids in long-term treatments. Our approach to study drug resistance offers the potential to determine high priority treatments to test in animal models.

SUBMITTER: Thakuri PS

PROVIDER: S-EPMC7088992 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Synergistic Inhibition of Kinase Pathways Overcomes Resistance of Colorectal Cancer Spheroids to Cyclic Targeted Therapies.

Thakuri Pradip Shahi PS Gupta Megha M Joshi Ramila R Singh Sunil S Tavana Hossein H

ACS pharmacology & translational science 20190719 4

Cancer cells often adapt to single-agent treatments with chemotherapeutics. Activation of alternative survival pathways is a major mechanism of drug resistance. A potential approach to block this feedback signaling is using combination treatments of a pair of drugs, although toxicity has been a limiting factor. Preclinical tumor models to identify mechanisms of drug resistance and determine low but effective combination doses are critical to effectively suppress tumor growth with reduced toxicit ...[more]

PMID: 32259061

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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

Synergistic Inhibition of Kinase Pathways Overcomes Resistance of Colorectal Cancer Spheroids to Cyclic Targeted Therapies.

Publications

Synergistic Inhibition of Kinase Pathways Overcomes Resistance of Colorectal Cancer Spheroids to Cyclic Targeted Therapies.

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