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.