期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 140, 期 12, 页码 2455-+出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2020.03.972
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资金
- Deutsche Forschungsgemeinschaft (DFG) [DFG SCHM2460/3-1, DFG SCHM2460/2-1]
Cutaneous melanoma is a highly malignant tumor typically driven by somatic mutation in the oncogenes BRAF or NRAS, leading to uncontrolled activation of the MEK/ERK MAPK pathway. Despite the availability of immunotherapy, MAPK pathway-targeting regimens are still a valuable treatment option for BRAF-mutant melanoma. Unfortunately, patients with NRAS mutation do not benefit from such therapies owing to the lack of targetable BRAF mutations and a high degree of intrinsic and acquired resistance toward MEK inhibition. Here, we demonstrate that concomitant inhibition of ERK5 removes this constraint and effectively sensitizes NRASmutant melanoma cells for MAPK pathway-targeting therapy. Using approved MEK inhibitors or a pharmacologic ERK inhibitor, we demonstrate that MAPK inhibition triggers a delayed activation of ERK5 through a PDGFR inhibitor-sensitive pathway in NRAS-mutant melanoma cells, resulting in sustained proliferation and survival. ERK5 phosphorylation also occurred naturally in NRAS-mutant melanoma cells and correlated with nuclear localization of its stem cell-associated effector KLF2. Importantly, MEK/ERK5 co-inhibition prevented long-term growth of human NRAS-mutant melanoma cells in vitro and effectively repressed tumor progression in a xenotransplant mouse model. Our findings suggest MEK/ERK5 cotargeting as a potential treatment option for NRAS-mutant melanoma, which currently is not amenable for targeted therapies.
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