Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology. Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology. See related commentary by Wainberg, p. 1369.

Translational Research on Caregiver Reading and Playing Behaviors: Evidence from an In Vivo Community-based Intervention throughout the COVID-19 Pandemic.

This study provides a rigorous assessment of a community-based early child development (ECD) intervention to understand the drivers of caregivers' reading and playing practices in a low-resourced township in South Africa. Mentors visited 157 homes biweekly (2474 observations from 2019-21; children ages 0-5), completing surveys regarding caregiver behaviors and engagement. One hundred and fifty-seven caregivers (mostly Black, Zulu women) participated in the program during this time period and completed surveys biannually on their support system (modified version of the Multidimensional Scale of Perceived Support) and ECD beliefs (modified versions of the Parental Play Beliefs Scale and the Parent Opinion Survey). Longitudinal Hierarchical Linear Model revealed that several behaviors and beliefs significantly predicted positive parenting behaviors. Regression discontinuity plots suggest that positive parenting behaviors could continue and even improve following Covid-19 shutdowns, especially in homes with more intervention visits. This paper provides translational evidence on tangible ways interventions can engage caregivers in stimulating ECD behaviors.