Cellular cartography reveals mouse prostate organization and determinants of castration resistance.

Inadequate response to androgen deprivation therapy (ADT) frequently arises in prostate cancer, driven by cellular mechanisms that remain poorly understood. Here, we integrated single-cell RNA sequencing, single-cell multiomics, and spatial transcriptomics to define the transcriptional, epigenetic, and spatial basis of cell identity and castration response in the mouse prostate. Leveraging these data along with a meta-analysis of human prostates and prostate cancer, we identified cellular orthologs and key determinants of ADT response and resistance.

SMARCA4 Deficient Gastric Carcinoma With Squamous Differentiation in a Young Patient With Aggressive Clinical Course.

Inactivation of (BRG1), a subunit of SWI/SNF complex, has been reported in malignancies from various sites, including the thorax, uterus, ovary, and gastrointestinal tract, and is usually associated with aggressive clinical course. These tumors have been reported primarily in elderly patients and on histology demonstrate high-grade morphology, often with rhabdoid differentiation. SMARCA4 loss is exceedingly rare in primary gastric cancers.

The UBA1-STUB1 axis mediates cancer immune escape and resistance to checkpoint blockade.

How cancer cells escape immune surveillance and resist immune checkpoint blockade (ICB) remains to be fully elucidated. By screening candidate genes frequently gained in cancer, we identified expression of ubiquitin-like modifier activating enzyme 1 (UBA1) as being the most negatively correlated with signatures related to effector CD8+ T-cells. High UBA1 expression was strongly predictive of treatment resistance and poor survival in ICB cohorts.

Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader.