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Ref Type Journal Article
PMID (27048951)
Authors Feng JH, Nakagawa-Goto K, Lee KH, Shyur LF
Title A Novel Plant Sesquiterpene Lactone Derivative, DETD-35, Suppresses BRAFV600E Mutant Melanoma Growth and Overcomes Acquired Vemurafenib Resistance in Mice.
Journal Molecular cancer therapeutics
Vol 15
Issue 6
Date 2016 Jun
URL
Abstract Text Acquired resistance to vemurafenib develops through reactivation of RAF/MEK/ERK signaling or bypass mechanisms. Recent combination therapies such as a MEK inhibitor combined with vemurafenib show improvement in major clinical end points, but the percentage of patients with adverse toxic events is higher than with vemurafenib monotherapy and most patients ultimately relapse. Therefore, there is an urgent need to develop new antimelanoma drugs and/or adjuvant agents for vemurafenib therapy. In this study, we created a novel semiorganically modified derivative, DETD-35, from deoxyelephantopin (DET), a plant sesquiterpene lactone demonstrated as an anti-inflammatory and anti-mammary tumor agent. Our results show that DETD-35 inhibited proliferation of a panel of melanoma cell lines, including acquired vemurafenib resistance A375 cells (A375-R) established in this study, with superior activities to DET and no cytotoxicity to normal melanocytes. DETD-35 suppressed tumor growth and reduced tumor mass as effectively as vemurafenib in A375 xenograft study. Furthermore, DETD-35 also reduced tumor growth in both acquired (A375-R) and intrinsic (A2058) vemurafenib resistance xenograft models, where vemurafenib showed no antitumor activity. Notably, the combination of DETD-35 and vemurafenib exhibited the most significant effects in both in vitro and in vivo xenograft studies due to synergism of the compound and the drug. Mechanistic studies suggested that DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells. Overall, our results suggest that DETD-35 may be useful as a therapeutic or adjuvant agent against BRAF(V600E) mutant and acquired vemurafenib resistance melanoma. Mol Cancer Ther; 15(6); 1163-76. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
DETD-35 DETD-35 is a derivative of plant sesquiterpene lactone that inhibits Mek-Erk signaling and induces reactive oxygen species generation, which may lead to apoptosis in tumor cells (PMID: 27048951).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss melanoma sensitive DETD-35 + Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, DETD-35 and Zelboraf (vemurafenib) combination treatment resulted in further reduction of tumor size in cell line xenograft models of Zelboraf (vemurafenib)-resistant melanoma harboring PTEN loss when compared to single agent treatment (PMID: 27048951). 27048951
PTEN loss melanoma sensitive DETD-35 Preclinical - Cell line xenograft Actionable In a preclinical study, DETD-35 treatment resulted in reduced tumor size in cell line xenograft models of Zelboraf (vemurafenib)-resistant melanoma harboring PTEN loss (PMID: 27048951). 27048951
BRAF V600E melanoma sensitive DETD-35 Preclinical - Cell line xenograft Actionable In a preclinical study, DETD-35 inhibited proliferation and colony formation of melanoma cells harboring BRAF V600E in culture and reduced tumor size in xenograft models (PMID: 27048951). 27048951
BRAF V600E melanoma sensitive DETD-35 + Vemurafenib Preclinical - Cell line xenograft Actionable In a preclinical study, DETD-35 and Zelboraf (vemurafenib) synergistically inhibited proliferation and colony formation of melanoma cells harboring BRAF V600E in culture and reduced tumor size in xenograft models (PMID: 27048951). 27048951