In silico & in vitro approaches suggest osteoclastogenesis induction underlying fractures in Entrectinib-treated children.

ABSTRACT: Entrectinib, a potent, CNS-active, TRK and ROS1 inhibitor is associated with occurrence of bone fractures, particularly in pediatric patients. We embarked on computer-guided and experimental investigations to identify the underlying mechanism that should help safe dosing of children receiving this drug. An artificial intelligence (AI)-based approach was used to allow for hypothesis generation regarding drug effects in a clinical setting and mechanistic insights on safety and efficacy. This was followed by confirmatory in vitro studies using human bone cell cultures. The AI-based hypothesis suggested an effect via inhibition of TRK and JAK2, as molecular targets of Entrectinib, underlying the fractures. Subsequent experiments using human bone cells showed that Entrectinib reduced markers of

SUBMITTER: Ehnert S 

PROVIDER: S-EPMC12454534 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature