Abstract B175: A novel plant sesquiterpene lactone derivative DETD suppresses BRAFV600E mutant melanoma growth and overcomes acquired vemurafenib resistance in mice
Authors: Feng Jia-Hua , Nakagawa-Goto Kyoko , Lee Kuo-Hsiung , Shyur Lie-Fen 
Published: May 2016

Melanoma is the most lethal form of skin cancer and cases are increasing year by year. BRAFV600E mutation is found approximately in 50% of melanoma patients that drives MAPK (RAF/MEK/ERK) signaling for cancer progression. Vemurafenib, a small molecule that specifically targets BRAFV600E mutation, received FDA approval for treatment of late-stage melanoma in 2011. Unfortunately, patients develop acquired vemurafenib resistance via reactivation of MAPK signaling or bypass mechanisms. Recent combination therapy such as MEK inhibitor combined with vemurafenib shows improvement in major clinical end points but percentage of patients with adverse toxic events are higher compared to vemurafenib monotherapy and most patients relapse ultimately. It is therefore an urgent need to develop new anti-melanoma drug and/or adjuvant agent for vemurafenib therapy. In this study, we created a novel semi-organically modified derivative DETD from deoxyelephantopin (DET), a plant sesquiterpene lactone demonstrated as an anti-inflammatory and anti-mammary tumor agent in our laboratory. DETD suppressed both parental human BRAFV600E mutant melanoma (A375) and vemurafenib resistance melanoma (A375-R) cell proliferation in vitro. Furthermore, through compound drug combination assay, DETD and vemurafenib was found to show synergism in suppressing proliferation, conoly formation and inducing apoptosis of A375 melanoma cell. In A375 xenograft study, DETD suppressed tumor growth and reduced tumor mass by 70.5%, as effective as vemurafenib (71.9%), compared to tumor control group. Moreover, compound-drug combinational treatment with alternate administration of DETD and vemurafenib also showed similar tumor growth inhibition efficacy by 72.3%, suggesting in vivo synergistic or additive effect of DETD and vemurafenib. In A375-R xenograft study, vemurafenib treatment showed little or no anti-tumor activity with similar tumor growth rate and sizes relative to the tumor control group, whereas DETD could reduce A375-R tumor growth and mass with 46.9%. Notably, the combination of DETD and vemurafenib treatment exhibited the most significant effect, with a 65.3% reduction in tumor mass. Our mechanistic studies revealed the activation of non-receptor tyrosine kinase Src and its downstream signaling pathways, including MAPK, Akt and STAT3 pathways in the vemurafenib resistant melanoma A375-R, and DETD could de-regulate the activation of all these multi- kinase signaling pathways. Overall, our results offer strong evidence of DETD in inhibiting BRAFV600E melanoma growth and its acquired vemurafenib resistance in mice that suggest DETD might have great therapeutic or adjuvant potential in management of melanoma patients with BRAFV600E mutation.

Citation Format: Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. A novel plant sesquiterpene lactone derivative DETD suppresses BRAFV600E mutant melanoma growth and overcomes acquired vemurafenib resistance in mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B175.