Bowel

This study investigates strategies to overcome drug resistance in gastrointestinal stromal tumors (GIST) driven by oncogenic KIT and PDGFRA mutations. Current tyrosine kinase inhibitors (TKIs) face limitations due to off-target toxicities and resistance mutations. Researchers employed a structure-based scaffold-hopping approach to design novel selective inhibitors. Their structure-activity relationship studies and 14 co-crystal structures, including one for PDGFRA-G680R, helped define key molecular interactions underlying resistance and selectivity. The developed 6,7-quinazoline-based inhibitors demonstrate high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling.

This study investigated the dynamics of circulating tumor cells (CTCs) in 18 patients with advanced KRASG12C-mutated solid tumors treated with glecirasib, a KRASG12C inhibitor. Researchers observed an evolution in CTC subtypes (epithelial, mesenchymal, mixed) during treatment, particularly an increase in mixed CTCs at progression. Baseline CTC levels and their changes correlated with progression-free survival and overall survival. Furthermore, adding local radiotherapy for progressive lesions in patients with more than one CTC at progression significantly prolonged survival.