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A method for overcoming plasma protein inhibition of tyrosine kinase inhibitors.

ABSTRACT: FMS-like tyrosine kinase 3 (FLT3) is the most frequently-mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKI have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma protein binding of FLT3 TKI, specifically staurosporine-derivatives (STS-TKI) by alpha-1-acid glycoprotein (AGP); simulating its effects upon drug efficacy. Human AGP inhibits the anti-proliferative activity of STS-TKI in FLT3-ITD-dependent cells, with IC₅₀ shifts higher than clinically achievable. This is not seen with non-human plasma. Mifepristone co-treatment, with its higher AGP affinity, improves TKI activity despite AGP, yielding IC₅₀s predicted to be clinically effective. In a mouse model of AGP drug inhibition, mifepristone restores midostaurin activity. This suggests combinatorial methods for overcoming plasma protein inhibition of existing TKIs for leukemia as well as providing a platform for investigating the drug-protein interaction space for developing more potent small-molecule agents.

SUBMITTER: Young DJ

PROVIDER: S-EPMC8478262 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A method for overcoming plasma protein inhibition of tyrosine kinase inhibitors.

Young David J DJ Nguyen Bao B Li Li L Higashimoto Tomoyasu T Levis Mark J MJ Liu Jun O JO Small Donald D

Blood cancer discovery 20210702 5

FMS-like tyrosine kinase 3 (FLT3) is the most frequently-mutated gene in acute myeloid leukemia and a target for tyrosine kinase inhibitors (TKI). FLT3 TKI have yielded limited improvements to clinical outcomes. One reason for this is TKI inhibition by endogenous factors. We characterized plasma protein binding of FLT3 TKI, specifically staurosporine-derivatives (STS-TKI) by alpha-1-acid glycoprotein (AGP); simulating its effects upon drug efficacy. Human AGP inhibits the anti-proliferative acti ...[more]

PMID: 34589716

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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.

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A method for overcoming plasma protein inhibition of tyrosine kinase inhibitors.

Publications

A method for overcoming plasma protein inhibition of tyrosine kinase inhibitors.

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