Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, and Lie-Fen Shyur* (2016) A novel plant sesquiterpene lactone derivative DETD-35 suppresses BRAFV600E mutant melanoma growth and overcomes acquired vemurafenib resistance in mice. Molecular Cancer Therapeutics, 15(6):1163-1176
Acquired resistance to vemurafenib (PLX4032), a chemotherapeutic drug targeting BRAFV600E mutant melanoma, is developed frequently through reactivation of RAF/MEK/ERK signaling or bypass mechanisms. Current combination therapy (e.g., MEK inhibitor plus vemurafenib) shows improvement in major clinical end points but percentage of patients with adverse toxic events are higher than 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. We created a novel semi-organically modified derivative DETD-35 from a plant sesquiterpene lactone deoxyelephantopin (DET), which showed potent effect against both parental human BRAFV600E mutant melanoma (A375) and vemurafenib resistance melanoma (A375-R) cell proliferation in vitro and no cytotoxicity to normal melanocyte. DETD-35 inhibited BRAFV600E mutant melanoma growth as effective as FDA approval drug vemurafenib and overcame both intrinsic and acquired vemurafenib resistance in mouse xenograft. Notably, the combination of DETD-35 and vemurafenib exhibited synergism and showed the most significant effects in both in vitro and xenograft mouse models compared to the monotherapy. Mechanistic studies revealed that DETD-35 triggered ROS-induced apoptotic cell death in both A375 and A375-R melanoma cells and overcamed acquired vemurafenib resistance through inhibition of the MEK-ERK, Akt, and STAT3 signaling pathways. Overall, our data suggest the great therapeutic or adjuvant potential of DETD-35 in management of melanoma patients with BRAFV600E mutation. The published article was selected as the “Highlights” of the issue in the journal “Molecular Cancer Therapeutics”; in addition, one ROC patent is issued and USA/PCT patents are pending.
2017/08/21 10:30 AM
Dr. Chia-Lin Chung (Associate Professor, Department of Plant Pathology and Microbiology, National Taiwan University)
Bakanae of rice: new insights into an emerging old disease
Dr. Chung uses quantitative genetics approaches such as linkage mapping and genome-wide association mapping, in combined with molecular markers or whole-genome sequencing analysis, to dissect defense mechanisms against blast and bakanae disease in rice.
Auditorium A134, Agricultural Technology Building, Agricultural Biotechnology Research Center 2017/08/28 10:30 AM
Dr. Ho-Ming Chen (Assistant Research Fellow, Agricultural Biotechnology Research Center, Academia Sinica)
Toward RNA interference 2.0: new insights into the biogenesis, action, and movement of plant small RNA
Auditorium A134, Agricultural Technology Building, Agricultural Biotechnology Research Center