A Novel Human SDHA-Knockout Cell Line Model for the Functional Analysis of Clinically Relevant SDHA Variants.

Purpose: SDHA mutations are the most common cause of succinate dehydrogenase (SDH)-deficient GIST. Enhanced cancer surveillance of individuals carrying a known pathogenic germline SDHA mutation has the potential to detect early-stage tumors, allowing for improved patient outcomes. However, more than 95% of the >1,000 SDHA missense variants listed in ClinVar are variants of uncertain significance.

New treatment strategies for advanced-stage gastrointestinal stromal tumours.

When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease.

Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases.

Mutations within the activation loop of members of the class III receptor tyrosine kinase (RTK) subfamily, which includes KIT, PDGFRA, and FLT3, have been observed in multiple human tumor types. These mutations confer constitutive activation as well as resistance to the type II tyrosine kinase inhibitors (TKI) that are currently clinically available, such as imatinib and sunitinib. It is now understood that activation loop mutations in class III RTKs shift the activation state equilibrium away from inactive states, to which type II TKIs bind, to the active state by destabilizing the inactive conformation.