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MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib.

MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib.
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Ninomiya K, Ohashi K, Makimoto G, Tomida S, Higo H, Kayatani H, Ninomiya T, Kubo T, Ichihara E, Hotta K, Tabata M, Maeda Y, Kiura K,


Ninomiya K, Ohashi K, Makimoto G, Tomida S, Higo H, Kayatani H, Ninomiya T, Kubo T, Ichihara E, Hotta K, Tabata M, Maeda Y, Kiura K, (click to view)

Ninomiya K, Ohashi K, Makimoto G, Tomida S, Higo H, Kayatani H, Ninomiya T, Kubo T, Ichihara E, Hotta K, Tabata M, Maeda Y, Kiura K,

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Scientific reports 2018 01 318(1) 1955 doi 10.1038/s41598-018-20326-z
Abstract

As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation; however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells; the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

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