Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision

SIMPLE SUMMARY: Gastrointestinal stromal tumors (GISTs) are rare malignancies of the gastrointestinal tract recognized by their clinical presentation and using specific immunohistochemical staining for CD117 and DOG1. In recent years, prognoses of GISTs patients have significantly improved due to the introduction of tyrosine kinase inhibitors (TKIs) in clinical practice. KIT/PDGFRA-activating mutations are major driver alterations in the development of GISTs, leading to ligand-independent activation of KIT/PDGFRA receptors. The activated KIT/PDGFRA receptor is sensitive to the TKI imatinib. However, not all GIST patients respond to imatinib. Precise characterization of the driver mutations in GISTs—in particular, in the KIT and PDGFRA genes—and an understanding of the molecular mechanisms underlying resistance to imatinib and other TKIs should allow clinicians to select the most effective targeted drug as part of regular clinical practice. The correct choice of the TKI in the sequence of targeted agents should lead to improved survival for metastatic patients. ABSTRACT: Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.