Abstract
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR–TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure–activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.
Highlights
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-threonine at position 790 with methionine (T790M), the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs)
In cases without the cysteine at position 797 with serine (C797S) mutation, loss of T790M was reported as specific resistant mechanism to third-generation EGFR–TKIs, bypass pathway activation, such as c-MET activation or small-cell lung cancer (SCLC) transformation, in resistant tumours is thought to be the mechanism of resistance similar to that known in first-generation EGFR–TKIs33–39
Gefitinib and erlotinib are so-called first-generation EGFR–TKIs that were proven to be efficacious for Non-small-cell lung cancer (NSCLC) harbouring an EGFR mutation (EGFR-activating mutation; exon 19 deletion [del19] or L858R point mutation in exon 21 [L858R])
Summary
Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs). Many clinical trials of various agents to overcome the acquired resistance to gefitinib or erlotinib were tried but failed to show any clinical advantage, except for one trial in which afatinib þ cetuximab achieved a response rate of 29% (refs 20–25) Despite its efficacy, this combination treatment has not been used in the clinical setting because of its relatively severe toxicity. Janne et al.[30] reported that in a phase 1/2 trial of osimertinib, among 127 patients with confirmed EGFR T790M who could be evaluated, the response rate was 61% and the median progression-free survival was 9.6 months, which is as long as that of first-line EGFR–TKIs for EGFR-mutated lung cancer. New therapeutic strategies are needed to overcome the resistance to the third-generation EGFR–TKIs
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