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Lamellarin 14, a derivative of marine alkaloids, inhibits the T790M/C797S mutant epidermal growth factor receptor
Naoyuki Nishiya1, Yusuke Oku1, Chie Ishikawa1
1Division of Integrated Information for Pharmaceutical Sciences, Department of Clinical Pharmacy, Iwate Medical University School of Pharmacy, Yahaba, Japan.
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.
Insights
A new marine-derived compound, lamellarin 14, effectively targets the C797S mutant epidermal growth factor receptor (EGFR), overcoming resistance to current EGFR-tyrosine kinase inhibitors (TKIs). This discovery offers a promising strategy against acquired resistance in cancer therapy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- Acquired resistance to molecularly targeted kinase inhibitors is a significant clinical challenge.
- The C797S mutation in epidermal growth factor receptor (EGFR) confers resistance to third-generation EGFR-tyrosine kinase inhibitors (TKIs) like osimertinib.
Purpose of the Study:
- To develop a novel class of EGFR-TKIs effective against resistance mutations.
- To investigate the potential of derivatized marine alkaloids as EGFR-TKIs.
Main Methods:
- Derivatization of the marine alkaloid lamellarin N to create new EGFR-TKI candidates.
- Bioinformatic analyses to assess changes in biological activity.
- In vitro studies using Ba/F3 and PC-9 cell lines with specific EGFR mutations (del ex19/T790M/C797S).
- In vivo efficacy assessment in a mouse xenograft model.
Main Results:
- Lamellarin 14, a novel derivative, demonstrated efficacy against the C797S mutant EGFR.
- Bioinformatic analysis indicated a shift from topoisomerase inhibition to kinase inhibition activity.
- Lamellarin 14 showed sensitivity in cells with EGFR del ex19/T790M/C797S mutations, comparable to cells with earlier resistance mutations.
- In vivo studies confirmed lamellarin 14's ability to suppress tumor growth in a relevant mouse model.
Conclusions:
- Lamellarin 14 represents a new structural class of EGFR-TKIs.
- This compound effectively targets EGFR with the C797S resistance mutation.
- Lamellarin 14 holds potential for preventing cross-resistance to existing EGFR-TKIs in cancer treatment.
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