Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor
© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:112 |
|---|---|
| Enthalten in: |
Cancer science - 112(2021), 5 vom: 01. Mai, Seite 1963-1974 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Nishiya, Naoyuki [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 10.05.2021 Date Revised 03.06.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1111/cas.14839 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM321055071 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM321055071 | ||
| 003 | DE-627 | ||
| 005 | 20231225175010.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1111/cas.14839 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1070.xml |
| 035 | |a (DE-627)NLM321055071 | ||
| 035 | |a (NLM)33544933 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Nishiya, Naoyuki |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 10.05.2021 | ||
| 500 | |a Date Revised 03.06.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a epidermal growth factor receptor | |
| 650 | 4 | |a lung cancer | |
| 650 | 4 | |a recurrence | |
| 650 | 4 | |a topoisomerase inhibitor | |
| 650 | 4 | |a tyrosine kinase inhibitor | |
| 650 | 7 | |a Acrylamides |2 NLM | |
| 650 | 7 | |a Aniline Compounds |2 NLM | |
| 650 | 7 | |a Fluoroacetates |2 NLM | |
| 650 | 7 | |a Heterocyclic Compounds, 4 or More Rings |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a lamellarin 14 |2 NLM | |
| 650 | 7 | |a lamellarin 3 |2 NLM | |
| 650 | 7 | |a lamellarin N |2 NLM | |
| 650 | 7 | |a osimertinib |2 NLM | |
| 650 | 7 | |a 3C06JJ0Z2O |2 NLM | |
| 650 | 7 | |a EGFR protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a ErbB Receptors |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 700 | 1 | |a Oku, Yusuke |e verfasserin |4 aut | |
| 700 | 1 | |a Ishikawa, Chie |e verfasserin |4 aut | |
| 700 | 1 | |a Fukuda, Tsutomu |e verfasserin |4 aut | |
| 700 | 1 | |a Dan, Shingo |e verfasserin |4 aut | |
| 700 | 1 | |a Mashima, Tetsuo |e verfasserin |4 aut | |
| 700 | 1 | |a Ushijima, Masaru |e verfasserin |4 aut | |
| 700 | 1 | |a Furukawa, Yoko |e verfasserin |4 aut | |
| 700 | 1 | |a Sasaki, Yuka |e verfasserin |4 aut | |
| 700 | 1 | |a Otsu, Keishi |e verfasserin |4 aut | |
| 700 | 1 | |a Sakyo, Tomoko |e verfasserin |4 aut | |
| 700 | 1 | |a Abe, Masanori |e verfasserin |4 aut | |
| 700 | 1 | |a Yonezawa, Honami |e verfasserin |4 aut | |
| 700 | 1 | |a Ishibashi, Fumito |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuura, Masaaki |e verfasserin |4 aut | |
| 700 | 1 | |a Tomida, Akihiro |e verfasserin |4 aut | |
| 700 | 1 | |a Seimiya, Hiroyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Yamori, Takao |e verfasserin |4 aut | |
| 700 | 1 | |a Iwao, Masatomo |e verfasserin |4 aut | |
| 700 | 1 | |a Uehara, Yoshimasa |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer science |d 2003 |g 112(2021), 5 vom: 01. Mai, Seite 1963-1974 |w (DE-627)NLM12479498X |x 1349-7006 |7 nnns |
| 773 | 1 | 8 | |g volume:112 |g year:2021 |g number:5 |g day:01 |g month:05 |g pages:1963-1974 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1111/cas.14839 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 112 |j 2021 |e 5 |b 01 |c 05 |h 1963-1974 | ||