JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression

Oncogenic KRAS has been difficult to target and currently there is no KRASbased targeted therapy available for patients suffering from KRASdriven lung adenocarcinoma (AC). Alternatively, targeting KRASdownstream effectors, KRAScooperating signaling pathways or cancer hallmarks, such as tumorpromoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAKSTAT pathway is considered to be a central player in inflammationmediated tumorigenesis, we investigated here the implication of JAKSTAT signaling and the therapeutic potential of JAK1/2 inhibition in KRASdriven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAKSTAT signaling correlated with disease progression and KRAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of KRASdriven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumorpromoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for KRASdriven lung AC.(VLID)510233

Pollution in an urban Bayou: Magnitude, spatial distribution and origin

Bayou Texar in Pensacola, FL, receives pollutants from a variety of sources, presumably including two USEPA\u27s Priorities List sites. To evaluate the potential negative impacts of pollution in this type of setting, we determined the level and distribution of some of the pollutants in the bayou and identified the most likely sources for them. Results show that fluoride, a tracer for a contaminated groundwater plume from one of the Priorities List sites, enters sediments in the northern part of the bayou and migrates into the water. Radium in the bayou most likely also emanates from the contaminated groundwater plume. However, 228Ra/226Ra isotope ratios indicate that the radium enters the plume from the aquifer matrix, and thus does not originate directly at the Priorities List site. PAHs of creosote origin are known to have been released by the second Priorities List site but apparently they do not affect the sediments of the bayou because ratios of individual PAHs show that they are derived from combustion. The concentrations of the PAHs are slightly higher in the northern part of the bayou. Unlike other pollutants, most metals exceed their probable effects level (PEL) in many places in the bayou. The highest concentrations are observed in the northern part of the bayou. Low metal concentrations in monitoring wells and in deep sediments in the bayou suggest that the metals do not come from the groundwater plume. Sediment transport analysis shows that sediments are trapped in the northern part of the bayou. Consequently, long term accumulation explains the observed high concentrations of heavy metals, and other sediment bound pollutants, in the northern part of Bayou Texar. Pollutant concentrations vary greatly spatially, demonstrating the importance of geographical analysis for this type of environmental research. © Springer 2006

Afatinib restrains K-RAS-driven lung tumorigenesis

On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth. However, EGFR inhibition initiates a rapid resistance mechanism involving non-EGFR ERBB family members. This tumor escape mechanism clarifies the disappointing outcome of first-generation TKIs and suggests high therapeutic potential of pan-ERBB inhibitors. On the basis of various experimental models including genetically engineered mouse models, patient-derived and cell line-derived xenografts, and in vitro experiments, we demonstrate that the U.S. Food and Drug Administration-approved pan-ERBB inhibitor afatinib effectively impairs K-RAS-driven lung tumorigenesis. Our data support reconsidering the use of pan-ERBB inhibition in clinical trials to treat K-RAS-mutated NSCLC