{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Nishiya N"],"funding":["Japan Society for the Promotion of Science"],"pagination":["1963-1974"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8088975"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["112(5)"],"pubmed_abstract":["The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR-TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor-like biological activity of lamellarin N into kinase inhibitor-like activity. Ba/F3 and PC-9 cells expressing the EGFR in-frame deletion within exon 19 (del ex19)/T790M/C797S triple-mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple-mutant EGFR PC-9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple-mutant EGFR PC-9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR-TKI that prevents the development of cross-resistance against known drugs in this class."],"journal":["Cancer science"],"pubmed_title":["Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor."],"pmcid":["PMC8088975"],"funding_grant_id":["JP 16H06276","JP 19K05715"],"pubmed_authors":["Sakyo T","Yamori T","Iwao M","Matsuura M","Fukuda T","Uehara Y","Mashima T","Yonezawa H","Dan S","Ishikawa C","Abe M","Furukawa Y","Otsu K","Nishiya N","Seimiya H","Sasaki Y","Tomida A","Oku Y","Ushijima M","Ishibashi F"],"additional_accession":[]},"is_claimable":false,"name":"Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor.","description":"The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR-TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor-like biological activity of lamellarin N into kinase inhibitor-like activity. Ba/F3 and PC-9 cells expressing the EGFR in-frame deletion within exon 19 (del ex19)/T790M/C797S triple-mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple-mutant EGFR PC-9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple-mutant EGFR PC-9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR-TKI that prevents the development of cross-resistance against known drugs in this class.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 May","modification":"2025-04-18T17:40:39.606Z","creation":"2025-04-07T05:17:16.733Z"},"accession":"S-EPMC8088975","cross_references":{"pubmed":["33544933"],"doi":["10.1111/cas.14839"]}}