An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy

Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, platinums) and a lack of targeted alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic oxfendazole. Surprisingly, oxfendazole acts via the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) immune responses. IRAK1 drives R-RT in a pathway involving IRAK4 and TRAF6 but not the IL-1R/TLR-IRAK adaptor MyD88. Rather than stimulating nuclear factor-κB, radiation-activated IRAK1 prevented apoptosis mediated by the PIDDosome complex (comprising PIDD, RAIDD and caspase-2). Countering this pathway with IRAK1 inhibitors suppressed R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Moreover, IRAK1 inhibitors synergized with inhibitors of PIN1, a prolyl isomerase essential for IRAK1 activation in response to pathogens and, as shown here, in response to ionizing radiation. These data identify an IRAK1 radiation-response pathway as a rational chemoradiation therapy target

Geographic access and the use of screening mammography

BACKGROUND: Screening mammography rates vary geographically and have recently declined. Inadequate mammography resources in some areas may impair access to this technology. We assessed the relationship between availability of mammography machines and the use of screening. METHODS: The location and number of all mammography machines in the US were identified from US Food and Drug Administration records of certified facilities. Inadequate capacity was defined as <1.2 mammography machines per 10,000 women aged 40 or older, the threshold required to meet the Healthy People 2010 target screening rate. The impact of capacity on utilization was evaluated in two cohorts: female respondents age 40 or older to the 2006 Behavioral Risk Factor Surveillance System survey (BRFSS) and a 5% nationwide sample of female Medicare beneficiaries age 65 or older in 2004–2005. RESULTS: About 9% of women in the BRFSS cohort and 13% of women in the Medicare cohort lived in counties with <1.2 mammography machines per 10,000 women age 40 or older. In both cohorts, residence in a county with inadequate mammography capacity was associated with lower odds of a recent mammogram (adjusted odds ratio [AOR] in BRFSS: 0.89, 95% CI 0.80 – 0.98, p<0.05; AOR in Medicare: 0.86, 95% CI 0.85 – 0.87, p<0.05), controlling for demographic and health care characteristics. CONCLUSION: In counties with few or no mammography machines, limited availability of imaging resources may be a barrier to screening. Efforts to increase the number of machines in low-capacity areas may improve mammography rates and reduce geographic disparities in breast cancer screening