NRAS overexpression

We also revealed a correlation between tumor-infiltrating immune cells in RAS mutated AML microenvironment. Our findings suggest that DUSP1 signaling pathways may regulate Ara-C sensitivity in AML.

This study aimed to explore the functional effects of NRAS Q61R overexpression in MM cell lines. The results showed that overexpression of NRAS Q61R negatively affects cell proliferation but increases cell migration and invasiveness. These findings suggest mechanisms by which NRAS Q61R may play a significant role in the progression and aggressiveness of MM.

There is no association between NRAS mutations and HER2 overexpression in colorectal cancer patients.

ARV-471 is an orally bioavailable cereblon (CRBN)-based PROteolysis-TArgeting Chimera (PROTAC®) small molecule that demonstrates superior ER degradation and anti-tumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER-positive breast cancer patients. CRBN knockout in ER+ breast cancer cells did not confer resistance to ARV-471, consistent with ARV-471 possessing ER antagonist activity independent of its degrader activity. Together, these data suggest that acquired resistance to ARV-471 may be associated with alterations within Receptor Tyrosine Kinase/MAPK signaling pathways rather than ER signaling or E3 ligase machinery.

Moreover, the NRAS demonstrated impact on the proliferation, apoptosis, and melanin production of melanocytes (P < 0.05), and the strong correlation of NRAS with melanin-related genes was evidently observed (P < 0.05). Our results suggested that NRAS can be used as a gene that regulates melanin production and controls melanocyte proliferation and apoptosis, providing a new theoretical basis for studying the mechanism of mammalian fur color formation.

Our study unveils DNASE1L3 as a novel HCC cell cycle regulator and tumor suppressor. DNASE1L3 impairs HCC tumorigenesis by delaying cell cycle progression possibly through disrupting the positive E2F1-CDK2 regulatory loop. DNASE1L3 may serve as a target for the development of novel therapeutic strategies against HCC.

These data suggest that elevated NRAS levels in DCIS are not only a marker but can also control the emergence of basal-like features leading to more aggressive tumor activity, thus supporting the therapeutic hypothesis that targeting NRAS and/or downstream pathways may block disease progression for a subset of DCIS patients with high NRAS.

Among putative ATE1 substrates is the tumor suppressor AXIN1, pointing to the possibility that ATE1 may fine-tune AXIN1 function in melanoma. Our findings highlight an unexpected role for ATE1 in melanoma cell aggressiveness and suggest that ATE1 constitutes a potential new therapeutic target.

These expression levels revealed that miRNA-145-5p and NRAS can be utilized as diagnostic biomarkers in colorectal cancer death. This may also introduce the microRNAs as colorectal cancer therapeutic targets.

Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regulation of stem cells, differentiation, proliferation, oxidative phosphorylation, mitochondrial function, and apoptosis; relevant in human disease. Spliceosome genes, found to be abnormal in MDS patients and downregulated in our HR-MDS model, such as Rsrc1 and Wbp4, were upregulated by the treatment, as were genes involved in epigenetic regulation, such as DNMT3A and B, upregulated upon disease progression and downregulated upon treatment.

LITES is a promising biomarker for predicting an impaired response in lung cancer patients and for clarifying the biological mechanism underlying ICB therapy.

Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS, was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.

Our work confirms astable interplay of liver inflammation, carbonyl stress mediated by α-dC, and upregulated RAGE expression on CD8 Tand natural killer (NK) cells in situ in NAFLD and HCC, as key factors/determinants in liver disease progression. The obtained findings underline the role of α-dC and RAGECD8 Tand RAGE NK cells as biomarkers and candidates for a local therapeutic intervention in NAFLD and malignant liver disease.

Here we report inhibition of growth and downstream RAS-MAPK signaling in neuroblastoma cells in response to treatment with the SHP2 inhibitors SHP099, II-B08, and RMC-4550...Combinations of SHP2 inhibitors with other RAS pathway inhibitors such as trametinib, vemurafenib, and ulixertinib were synergistic and reversed resistance to SHP2 inhibition in neuroblastoma in vitro and in vivo. Combinations of SHP2 inhibitors with other RAS pathway inhibitors such as trametinib, vemurafenib, and ulixertinib were synergistic and reversed resistance to SHP2 inhibition in NB in vitro and in vivo. These results suggest for the first time that combination therapies targeting SHP2 and other components of the RAS-MAPK pathway may be effective against conventional therapy-resistant relapsed NB, including those that have acquired NRAS mutations.

PDT caused down-regulation of NRAS, HRAS and BCL2 and over-expression of CASP3 and BAX genes at mRNA levels in HNSCC cell line. The present study raises the possibility that the role of MB on BCL2 down-regulation and BAX and CASP3 over-expression was higher than laser alone while it seems that laser alone was more effective than MB in HRAS and NRAS down-regulation.

When we combine prednisolone treatment with selumetinib or ruxolitinib, we observe that ruxolitinib only synergizes with prednisolone in IL7-dependent steroid resistant PDX samples in the presence of IL7. Moreover, our data proposes that this synergistic effect may (in part) depend on the anti-MAPK-ERK effect downstream of JAK1/2-inhibition. Combined, our study strongly supports the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507), and contributes to the optimization and stratification of newly designed T-ALL treatment regimens.

We observed that the viability of MEK-inhibitor resistant melanoma cells could be reduced by combined treatment of anisomycin and MEK-inhibition. Our study demonstrates that activating the p38α-MAPK14 pathway in the presence of oncogenic NRAS abrogates melanoma in vitro and in vivo.

Consistently, patients with JMML who had PTPN11, KRAS, and NRAS mutations and high expression of MORRBID manifested poor overall survival. Our results suggest that Morrbid contributes to JMML pathogenesis.

In patients harboring BRAF or NRAS mutations, PKCα overexpression is associated with an 11-fold increased risk of death. Thus, PKCα mRNA is a novel target of IMP1, which is commonly overexpressed in melanoma and is linked to poorer overall survival.