Zobrazení zdroje stránky Rahbekmcmahon9697

The fitness landscape of cancer clones was perturbed by mutation and treatment in vitro and in vivo.Colorectal cancer cells express hepcidin to accumulate iron, promoting nucleotide metabolism.HER3 missense mutations can inhibit response of tumor cells to HER2-targeted therapies.Pharmacologic inhibition of RNA splicing produces immunogenic neoepitopes driving T-cell expansion.We systematically reviewed and synthesized evidence on the impact of physical activity/exercise on cancer treatment efficacy. We included six preclinical and seven clinical studies. Exercise significantly enhanced the efficacy of chemotherapy and tamoxifen in seven of eight rodent models in either an additive, sensitizing, or synergistic manner. In clinical studies, preliminary evidence indicates that exercise during neoadjuvant, primary, and adjuvant treatment may enhance efficacy of cancer therapies; however, no clinical study was designed for this purpose. [https://www.selleckchem.com/products/compound-3i.html 66615inhibitor] Here we discuss the biological mechanisms of exercise-associated enhancement of therapeutic efficacy and propose future research directions to definitively examine the effects of exercise on cancer treatment and patient outcomes.The somatic landscape of the cancer genome results from different mutational processes represented by distinct "mutational signatures." Although several mutagenic mechanisms are known to cause specific mutational signatures in cell lines, the variation of somatic mutational activities in patients, which is mostly attributed to somatic selection, is still poorly explained. Here, we introduce a quantitative trait, mutational propensity (MP), and describe an integrated method to infer genetic determinants of variations in the mutational processes in 3,566 cancers with specific underlying mechanisms. As a result, we report 2,314 candidate determinants with both significant germline and somatic effects on somatic selection of mutational processes, of which, 485 act via cancer gene expression and 1,427 act through the tumor-immune microenvironment. These data demonstrate that the genetic determinants of MPs provide complementary information to known cancer driver genes, clonal evolution, and clinical biomarkers. SIGNIFICANCE The genetic determinants of the somatic mutational processes in cancer elucidate the biology underlying somatic selection and evolution of cancers and demonstrate complementary predictive power across cancer types.The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1 mutant lung tumors to platinum therapy, was validated using a large patient response dataset. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies.Nonsense-mediated RNA decay (NMD) is recognized as an RNA surveillance pathway that targets aberrant mRNAs with premature translation termination codons (PTC) for degradation; however, its molecular mechanisms and roles in health and disease remain incompletely understood. In this study, we developed a novel reporter system to accurately measure NMD activity in individual cells. A genome-wide CRISPR-Cas9 knockout screen using this reporter system identified novel NMD-promoting factors, including multiple components of the SF3B complex and other U2 spliceosome factors. Interestingly, cells with mutations in the spliceosome genes SF3B1 and U2AF1, which are commonly found in myelodysplastic syndrome (MDS) and cancers, have overall attenuated NMD activity. Compared to wild type cells, SF3B1 and U2AF1 mutant cells were more sensitive to NMD inhibition, a phenotype that is accompanied by elevated DNA replication obstruction, DNA damage, and chromosomal instability. Remarkably, the sensitivity of spliceosome mutant cells to NMD inhibition was rescued by overexpression of RNase H1, which removes R-loops in the genome. Together, these findings shed new light on the functional interplay between NMD and RNA splicing and suggest a novel synthetic lethal strategy for the treatment of MDS and cancers with spliceosome mutations.Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK -mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2 - Wilms tumor 1 (WT1) binding ability were responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.