Biology subjects

Orr, N.

Publications and source records attributed to Orr, N..

3 recordsLinked to original sources

bioRxiv2026

Mutant KRAS dosage contributes to heterogeneity in lung cancer therapeutic response

Oncogenic KRAS mutations promote tumorigenesis by constitutive activation of multiple, well-characterised signalling pathways. However, there is significant heterogeneity across mutant KRAS tumours in terms of mutation present, mutant allele abundance and downstream signalling strength. It is unclear whether these variations can impact responses to specific therapies. Here, we demonstrate that [~]20% of lung adenocarcinomas (LUAD) show an increase in mutant KRAS dosage (KRASmutant allele fraction > KRASwild-type). Furthermore, we show that KRAS mutant dosage can directly influence clinical outcome and therapeutic susceptibilities in lung cancer. Our findings show that mutant KRAS copy gains specifically affect platinum lung cancer response, promoting resistance to this standard-of-care therapy. Importantly, increases in KRAS mutant dosage are also associated with an increased vulnerability to pS6K inhibition, due to the unique metabolic rewiring of these cells. Together, we show that mutant KRAS dosage contributes to the phenotypic heterogeneity of mutant KRAS NSCLC and that assessment of mutant KRAS content or signalling strength can help optimise treatments strategies for these patients.

cancer biology↗

bioRxiv2023

SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression

microRNAs (miRNAs) inhibit mRNA translation initiation by recruiting the GIGYF2/4EHP translation repressor complex to the mRNA 5 cap structure. Viruses utilise miRNAs to impair the host antiviral immune system and facilitate viral infection by expressing their own miRNAs or co-opting cellular miRNAs. We recently reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encoded non-structural protein 2 (NSP2) interacts with GIGYF2. This interaction is critical for blocking translation of the Ifn1-b mRNA that encodes the cytokine Interferon-{beta}, and thereby impairs the host antiviral immune response. However, it is not known whether NSP2 also affects miRNA-mediated silencing. Here, we demonstrate the pervasive augmentation of the miRNA-mediated translational repression of cellular mRNAs by NSP2. We show that NSP2 interacts with Argonaute 2, the core component of the miRNA-Induced Silencing Complex (miRISC) and enhances the translational repression mediated by natural miRNA binding sites in the 3 UTR of cellular mRNAs. Our data reveal an additional layer of the complex mechanism by which SARS-CoV-2 and likely other coronaviruses manipulate the host gene expression program through co-opting the host miRNA-mediated silencing machinery.

cell biology↗

bioRxiv2018

Comparative validation of breast cancer risk prediction models and projections for future risk stratification

BackgroundWell-validated risk models are critical for risk stratified breast cancer prevention. We used the Individualized Coherent Absolute Risk Estimation (iCARE) tool for comparative model validation of five-year risk of invasive breast cancer in a prospective cohort, and to make projections for population risk stratification.\n\nMethodsPerformance of two recently developed models, iCARE-BPC3 and iCARE-Lit, were compared with two established models (BCRAT, IBIS) based on classical risk factors in a UK-based cohort of 64,874 women (863 cases) aged 35-74 years. Risk projections in US White non-Hispanic women aged 50-70 years were made to assess potential improvements in risk stratification by adding mammographic breast density (MD) and polygenic risk score (PRS).\n\nResultsThe best calibrated models were iCARE-Lit (expected to observed number of cases (E/O)=0.98 (95% confidence interval [CI]=0.87 to 1.11)) for women younger than 50 years; and iCARE-BPC3 (E/O=1.00 (0.93 to 1.09)) for women 50 years or older. Risk projections using iCARE-BPC3 indicated classical risk factors can identify ~500,000 women at moderate to high risk (>3% five-year risk). Additional information on MD and a PRS based on 172 variants is expected to increase this to ~3.6 million, and among them, ~155,000 invasive breast cancer cases are expected within five years.\n\nConclusionsiCARE models based on classical risk factors perform similarly or better than BCRAT or IBIS. Addition of MD and PRS can lead to substantial improvements in risk stratification. Independent prospective validation of integrated models is needed prior to clinical evaluation risk stratified breast cancer screening and prevention.

epidemiology↗