Targeting ETV1 in Gastrointestinal Stromal Tumors: Tripping the Circuit Breaker in GIST?

Abstract

Summary: Activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes are the key oncogenic drivers in the majority of gastrointestinal stromal tumors (GIST), but novel results now show that aberrant kinase signaling is potentiated by a positive feedback circuit that involves the ETS transcription factor ETV1. Targeting ETV1 can disrupt this circuit and represents a promising new therapeutic approach for the treatment of GISTs.See related article by Ran and colleagues, p. 304 (5).Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract and one of the most common subtypes of sarcomas. Because of their unique molecular properties, GISTs spearheaded the use of targeted therapies in solid tumors, a concept that eventually led to a paradigm shift in oncologic therapy. GISTs were the fi rst solid tumor entity that could successfully be treated with small-molecule inhibitors, specifi cally tyrosine kinase inhibitors such as imatinib mesylate (Gleevec; ref. 1 ). This notion came shortly after the discovery that an oncogenic mutation in the KIT (75%-85%) or PDGFRA (platelet-derived growth factor receptor alpha; 5%-7%) gene is the tumor-initiating event in the vast majority of GISTs and leads to constitutive activation of the encoded receptor tyrosine kinase ( 2, 3 ). Major responses are seen after fi rst-line treatment with the KIT/PDGFRA inhibitor imatinib, and approximately 85% of patients with metastatic and/or inoperable GIST benefi t from this therapy. However, complete tumor remissions are rare, and about 50% of patients experience disease recurrence within 2 years of treatment. There are several reasons for this, including the emergence of secondary mutations in KIT/PDGFRA that confer drug resistance, entry into a state of cellular quiescence, and the potential existence of GIST stem/progenitor cells that express low levels of KIT and are intrinsically imatinib resistant. Given these reasons, it is unlikely that GISTs can be cured with imatinib alone, and additional therapeutic approaches are urgently needed.GISTs are thought to arise from a specialized cell type in the bowel wall, the interstitial cells of Cajal (ICC), or a common progenitor. These cells are present throughout the entire digestive tract, where they serve as pacemaker cells to coordinate peristalsis. Interestingly, there are several subsets of ICCs that are located in distinct microscopical locations within the gut, and only certain types seem to give rise to GIST. In an earlier study, Chi and colleagues ( 4 ) discovered that the ETV1 transcription factor is a master regulator not only of the ICC population giving rise to GIST, but also of an ICC-GIST-specifi c transcriptional network. ETV1 is highly expressed in GISTs (but not in other sarcomas) and is required for the growth and proliferation of GIST cells.A new study by the same group ( 5 ), published in this issue of Cancer Discovery , adds an important new spin to their previous observations. The latest data not only provide in vi...

Ripretinib and MEK Inhibitors Synergize to Induce Apoptosis in Preclinical Models of GIST and Systemic Mastocytosis

“…These studies demonstrate that both KIT-dependent and -independent pathways are active in some cases of GIST and these patients may not respond to KIT inhibition alone. Recent studies have shown that transcription factor ETV1 activates a positive feedback mechanism for KIT transcription and its levels are maintained by MAPK signaling pathway and PDGFRA signaling in KIT-mutant GIST (21,39,40).…”

Promoter capture Hi-C-based identification of recurrent noncoding mutations in colorectal cancer

“…Such discoveries facilitate the identification of novel therapeutic and chemoprevention agents, and classification of patients into molecular subgroups to personalise therapy. For example, it allows for the repositioning of ETV1 inhibitors, one of which has been employed in a clinical trial for gastrointestinal stromal tumours28,39.…”

ADRB2 Regulates the Proliferation and Metastasis of Gastrointestinal Stromal Tumor Cells by Enhancing the ETV1-c-KIT Signaling

“…Te ETV1-c-KIT signaling is the key positive feedback to promote GIST progression [19]. Our study reveals that ADRB2 is essential for ETV1-c-KIT feedback in GISTs.…”

“…We further explored the molecular mechanism of ADRB2 signalingmediated efects. ETV1-c-KIT signaling is a key positive feedback to promote GIST progression [19]. In ADRB2overexpressing GIST cells, ETV1, c-KIT, and p-ERK(Y204) expression were increased (Figure 5(a)).…”