Current research and treatment for gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have gained considerable research and treatment interest, especially in the last two decades. GISTs are driven by mutations commonly found in the KIT gene and less commonly in the platelet-derived growth factor receptor alpha gene, BRAF gene and succinate dehydrogenase gene. GISTs behave in a spectrum of malignant potential, and both the tumor size and mitotic index are the most commonly used prognostic criteria. Whilst surgical resection can offer the best cure, targeted therapy in the form of tyrosine kinase inhibitors (TKIs) has revolutionized the management options. As the first-line TKI, imatinib offers treatment for advanced and metastatic GISTs, adjuvant therapy in high-risk GISTs and as a neoadjuvant agent to downsize large tumors prior to resection. The emergence of drug resistance has altered some treatment options, including prolonging the first-line TKI from 1 to 3 years, increasing the dose of TKI or switching to second-line TKI. Other newer TKIs, such as sunitinib and regorafenib, may offer some treatment options for imatinib-resistant GISTs. New molecular targeted therapies are being evaluated, such as inhibitors of BRAF, heat shock protein 90, glutamine and mitogen-activated protein kinase signaling, as well as inhibitors of apoptosis proteins antagonist and even immunotherapy. This editorial review summarizes the recent research trials and potential treatment targets that may influence our future patient-specific management of GISTs. The current guidelines in GIST management from Europe, North America and Asia are highlighted.

Keywords: Gastrointestinal stromal tumors; KIT gene; Platelet-derived growth factor receptor alpha gene; BRAF gene; Succinate dehydrogenase gene; CD117; Tyrosine kinase inhibitor; Molecular targeted therapy

Core tip: Research in the histogenesis of gastrointestinal stromal tumors (GISTs) identified gene mutations in KIT, platelet-derived growth factor receptor alpha and BRAF. The discovery of tyrosine kinase inhibitors (TKIs) has allowed targeted therapy in metastatic and high-risk resected GISTs. However, the emergence of TKI-resistant GISTs has raised some important treatment issues. Newer TKIs and alternative targeted therapy within the domain of BRAF and the mitogen-activated protein kinase signaling pathway, heat shock protein 90 and succinate dehydrogenase inhibition are being investigated and appear promising. Many clinical trials have been undertaken and are still ongoing to define the best molecular targeted therapy for GISTs. The European, American and Asian guidelines on GISTs provide useful resources for specialists dealing with these interesting tumors.