MicroRNA-708 emerges as a potential candidate to target undruggable NRAS

Abstract

Abstract RAS (KRAS, NRAS, HRAS), the most frequently mutated oncogene in cancers, drives tumorigenesis by promoting cell proliferation, survival, and motility, was perceived undruggable for the past three decades. Intense research mainly focused on KRAS mutation, however, targeted therapy for NRAS mutation, which is frequently observed in several cancer types, including melanoma (15–20%), leukemia (10%), and occasionally other cancer types, remained an unmet medical need. Here we report using miRNA-708 that targets the distinct 3’ untranslated region (3’UTR) of NRAS to develop a miRNA-based precision medicine to treat NRAS mutation-driven cancers. We identify NRAS as a direct target of miRNA-708. Overexpression of miRNA-708 successfully reduced NRAS protein levels in NRAS-mutated melanoma, leukemia, and lung cancer cell line, resulting in suppressed cell proliferation, anchorage-independent growth, and promotion of reactive oxygen species-induced apoptosis. Consistent with the functional data, the activities of NRAS-downstream effectors, PI3K-AKT-mTOR or RAF-MEK-ERK signaling pathway, were impaired in miR-708 overexpressing cells. On the other hand, cell proliferation was not disturbed by miRNA-708 in cells carrying wildtype NRAS. Collectively, our data unveil the therapeutic potential of using miRNA-708 in NRAS mutation-driven cancer through direct depletion of constitutively active NRAS and thus inhibit its downstream effectors to decelerate cancer progression. Harnessing the beneficial effects of miR-708 may therefore offer a potential avenue for small RNA-mediated precision medicine in cancer treatment.