Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies found in the gastrointestinal tract. At a molecular level, most GISTs are characterized by gain-of-function mutations in V-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) and Platelet Derived Growth Factor Receptor Alpha (PDGFRA), leading to constitutive activated signaling through these receptor tyrosine kinases, which drive GIST pathogenesis. In addition to surgery, treatment with the tyrosine kinase inhibitor imatinib forms the mainstay of GIST treatment, particularly in the advanced setting. Nevertheless, the majority of GISTs develop imatinib resistance. Biomarkers that indicate metastasis, drug resistance and disease progression early on could be of great clinical value. Likewise, novel treatment strategies that overcome resistance mechanisms are equally needed. Non-coding RNAs, particularly microRNAs, can be employed as diagnostic, prognostic or predictive biomarkers and have therapeutic potential. Here we review which non-coding RNAs are deregulated in GISTs, whether they can be linked to specific clinicopathological features and discuss how they can be used to improve the clinical management of GISTs.

Keywords: GIST; biomarker; long non-coding RNAs; microRNA; therapy.

Figure 1

KIT receptor structure and KIT signaling. (A) The KIT proto-oncogene codes for a ~110 kDa transmembrane receptor tyrosine kinase KIT (CD117). KIT, together with Platelet Derived Growth Factor Receptor Alpha (PDGFRA), belongs to the type III tyrosine kinase receptor family and consists of 5 extracellular immunoglobulin (Ig)-like domains involved in KIT ligand (Stem Cell Factor, SCF) binding, a transmembrane domain, a juxtamembrane region and an intracellular kinase domain. Mutations in gastrointestinal stromal tumor (GIST) occur in exons that encode functional domains (arrows). (B) Constitutive KIT signaling as observed in GIST is transduced through the PI3K/AKT/mTOR, RAS-RAF-MAPK and JAK/STAT pathways thereby inhibiting apoptosis, promoting cell survival and proliferation.