KRAS G12C mutations in Asia: a landscape analysis of 11,951 Chinese tumor samples.

BACKGROUND: Kirsten rat sarcoma vial oncogene (KRAS) is one of the most prevalent oncogenes in multiple cancer types, but the incidence is different between the Asian and non-Asian populations. The recent development of KRAS G12C targeting drug has shown great promise. It is thus important to understand the genomic landscape of KRAS G12C in a specific population. METHODS: Sequencing data of 11,951 tumor samples collected from 11/2016 to 7/2019 from multiple centres in China were analyzed for KRAS mutation status. Concomitant genomic aberrations were further analyzed in tumors with KRAS G12C mutations, which were sequenced with comprehensive cancer panel including over 450 cancer-related genes. Smoking status and its correlation with KRAS were analyzed in 2,235 lung cancer cases within this cohort. RESULTS: KRAS mutations were identified in 1978 (16.6%) patient samples. Specifically, KRAS G12C accounted for 14.5% (n=286) of all KRAS mutations. G12C was most commonly seen in lung cancer (4.3%), followed by colorectal cancer (2.5%) and biliary cancer (2.3%). Almost all patients (99.6%) with G12C mutations had concomitant genomic aberrations. These were most commonly associated with the RAS/RTK pathway including BRAF and PI3KCA mutations. Moreover, KRAS mutation was positively correlated with smoking status in lung adenocarcinomas. CONCLUSIONS: The overall incidence of KRAS G12C mutations remains low in the Chinese population. The most common tumor types harboring KRAS G12C mutations are in patients suffering from lung, colorectal and biliary cancers.

Applied electric fields suppress osimertinib-induced cytotoxicity via inhibiting FOXO3a nuclear translocation through AKT activation.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor against T790M-mutant non-small cell lung cancer (NSCLC). Acquired resistance to osimertinib is a growing clinical challenge that is not fully understood. Endogenous electric fields (EFs), components of the tumor microenvironment, are associated with cancer cell migration and proliferation. However, the impact of EFs on drug efficiency has not been studied. In this study, we observed that EFs counteracted the effects of osimertinib. EFs of 100 mV/mm suppressed osimertinib-induced cell death and promoted cell proliferation. Transcriptional analysis revealed that the expression pattern induced by osimertinib was altered by EFs stimulation. KEGG analysis showed that differential expression genes were mostly enriched in PI3K-AKT pathway. Then, we found that osimertinib inhibited AKT phosphorylation, while EFs stimulation resulted in significant activation of AKT, which could override the effects generated by osimertinib. Importantly, pharmacological inhibition of PI3K/AKT by LY294002 diminished EF-induced activation of AKT and restored the cytotoxicity of osimertinib suppressed by EFs, which proved that AKT activation was essential for EFs to attenuate the efficacy of osimertinib. Furthermore, activation of AKT by EFs led to phosphorylation of forkhead box O3a (FOXO3a), and reduction in nuclear translocation of FOXO3a induced by osimertinib, resulting in decreased expression of Bim and attenuated cytotoxicity of osimertinib. Taken together, we demonstrated that EFs suppressed the antitumor activity of osimertinib through AKT/FOXO3a/Bim pathway, and combination of PI3K/AKT inhibitor with osimertinib counteracted the effects of EFs. Our findings provided preliminary data for therapeutic strategies to enhance osimertinib efficacy in NSCLC patients.

Cordycepin mitigates MPTP-induced Parkinson's disease through inhibiting TLR/NF-κB signaling pathway.

Parkinson's disease (PD) is a neurodegenerative disease with movement disorder. PD is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra. Cordycepin, a small molecule extracted from cordyceps sinensis, has neuroprotective, anti-inflammatory, antioxidant and anti-tumor properties. In this study, we explored its possible beneficial effects on PD. PD rat models and cell models were established via 1­methyl­4­phenyl­1,2,3,6­tetrahydropyridine (MPTP) injection and LPS treatment respectively, and cordycepin was administered. The motor functions of rats were examined, and the tyrosine hydroxylase (TH)-positive DA neurons and Iba1-positive microglia were detected by immunohistochemical and immunofluorescence staining. The expression levels of inflammatory and oxidative stress-related factors were also measured in vivo and in vitro. In addition, the TLR/NF-κB pathway was investigated to explore the mechanism. We found that in vivo, MPTP injection introduced motor disorders, the loss of DA neurons and the activation of TLR/NF-κB signaling pathway. Cordycepin treatment alleviated these MPTP-induced changes. In vitro, the results were confirmed in Lipopolysaccharide (LPS)-induced cells. Moreover, cordycepin mitigated the cytotoxic effects on PC12 cells produced by microglia. In conclusion, cordycepin alleviated PD symptoms by inhibiting TLR/NF-κB signaling pathway in vivo and in vitro.