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  • Title: Efficient Suppression of NRAS-Driven Melanoma by Co-Inhibition of ERK1/2 and ERK5 MAPK Pathways.
    Author: Adam C, Fusi L, Weiss N, Goller SG, Meder K, Frings VG, Kneitz H, Goebeler M, Houben R, Schrama D, Schmidt M.
    Journal: J Invest Dermatol; 2020 Dec; 140(12):2455-2465.e10. PubMed ID: 32376279.
    Abstract:
    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 NRAS-mutant 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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