Worldwide analysis of actionable genomic alterations in lung cancer and targeted pharmacogenomic strategies.

Based on data from the Global Cancer Statistics 2022, lung cancer stands as the most lethal cancer worldwide, with age-adjusted incidence and mortality rates of 23.6 and 16.9 per 100,000 people, respectively. Despite significant strides in precision oncology driven by large-scale international research consortia, there remains a critical need to deepen our understanding of the genomic landscape across diverse racial and ethnic groups. To address this challenge, we performed comprehensive in silico analyses and data mining to identify pathogenic variants in genes that drive lung cancer. We subsequently calculated the allele frequencies and assessed the deleteriousness of these oncogenic variants among populations such as African, Amish, Ashkenazi Jewish, East and South Asian, Finnish and non-Finnish European, Latino, and Middle Eastern. Our analysis examined 117,707 variants within 86 lung cancer-associated genes across 75,109 human genomes, uncovering 8042 variants that are known or predicted to be pathogenic. We prioritized variants based on their allele frequencies and deleterious scores, and identified those with potential significance for response to anti-cancer therapies through in silico drug simulations, current clinical pharmacogenomic guidelines, and ongoing late-stage clinical trials targeting lung cancer-driving proteins. In conclusion, it is crucial to unite global efforts to create public health policies that emphasize prevention strategies and ensure access to clinical trials, pharmacogenomic testing, and cancer research for these groups in developed nations.

The pharmacoepigenetic paradigm in cancer treatment.

Epigenetic modifications, characterized by changes in gene expression without altering the DNA sequence, play a crucial role in the development and progression of cancer by significantly influencing gene activity and cellular function. This insight has led to the development of a novel class of therapeutic agents, known as epigenetic drugs. These drugs, including histone deacetylase inhibitors, histone acetyltransferase inhibitors, histone methyltransferase inhibitors, and DNA methyltransferase inhibitors, aim to modulate gene expression to curb cancer growth by uniquely altering the epigenetic landscape of cancer cells. Ongoing research and clinical trials are rigorously evaluating the efficacy of these drugs, particularly their ability to improve therapeutic outcomes when used in combination with other treatments. Such combination therapies may more effectively target cancer and potentially overcome the challenge of drug resistance, a significant hurdle in cancer therapy. Additionally, the importance of nutrition, inflammation control, and circadian rhythm regulation in modulating drug responses has been increasingly recognized, highlighting their role as critical modifiers of the epigenetic landscape and thereby influencing the effectiveness of pharmacological interventions and patient outcomes. Epigenetic drugs represent a paradigm shift in cancer treatment, offering targeted therapies that promise a more precise approach to treating a wide spectrum of tumors, potentially with fewer side effects compared to traditional chemotherapy. This progress marks a step towards more personalized and precise interventions, leveraging the unique epigenetic profiles of individual tumors to optimize treatment strategies.

Integrated multi-omics analysis reveals the molecular interplay between circadian clocks and cancer pathogenesis.

Circadian rhythms (CRs) are fundamental biological processes that significantly impact human well-being. Disruption of these rhythms can trigger insufficient neurocognitive development, insomnia, mental disorders, cardiovascular diseases, metabolic dysfunctions, and cancer. The field of chronobiology has increased our understanding of how rhythm disturbances contribute to cancer pathogenesis, and how circadian timing influences the efficacy of cancer treatments. As the circadian clock steadily gains recognition as an emerging factor in tumorigenesis, a thorough and comprehensive multi-omics analysis of CR genes/proteins has never been performed. To shed light on this, we performed, for the first time, an integrated data analysis encompassing genomic/transcriptomic alterations across 32 cancer types (n = 10,918 tumors) taken from the PanCancer Atlas, unfavorable prognostic protein analysis, protein-protein interactomics, and shortest distance score pathways to cancer hallmark phenotypes. This data mining strategy allowed us to unravel 31 essential CR-related proteins involved in the signaling crossroad between circadian rhythms and cancer. In the context of drugging the clock, we identified pharmacogenomic clinical annotations and drugs currently in late phase clinical trials that could be considered as potential cancer therapeutic strategies. These findings highlight the diverse roles of CR-related genes/proteins in the realm of cancer research and therapy.

Computational Insights of the Interaction among Sea Anemones Neurotoxins and Kv1.3 Channel.

Sea anemone neurotoxins are peptides that interact with Na(+) and K(+) channels, resulting in specific alterations on their functions. Some of these neurotoxins (1ROO, 1BGK, 2K9E, 1BEI) are important for the treatment of about 80 autoimmune disorders because of their specificity for Kv1.3 channel. The aim of this study was to identify the common residues among these neurotoxins by computational methods, and establish whether there is a pattern useful for the future generation of a treatment for autoimmune diseases. Our results showed eight new key common residues between the studied neurotoxins interacting with a histidine ring and the selectivity filter of the receptor, thus showing a possible pattern of interaction. This knowledge may serve as an input for the design of more promising drugs for autoimmune treatments.